Benzene acetamide compounds useful as serine protease inhibitors

ABSTRACT

Compounds having the formula (I),  
                 
 
     and pharmaceutically-acceptable salts, hydrates, or prodrugs thereof, are useful as serine protease inhibitors, wherein X is —OH, —O(alkyl), —O(aryl), —O(arylalkyl), —NR 5 (aryl), or —NR 5 (arylalkyl); W is hydrogen or —(CR 7 R 8 ) q —W 1 ; W 1  is hydrogen or a bond with R 6 ; Z is a 5-membered heteroaryl group, a five to six membered heterocyclo or cycloalkyl group, a 9 to 10 membered bicyclic aryl or heteroaryl, or a six membered aryl or heteroaryl, and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 16  are as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the priority benefit of U.S.Provisional Application No. 60/446,578, filed Feb. 11, 2003, which isexpressly incorporated fully herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to benzene acetamide compounds thatare inhibitors of serine proteases such as Factor VIIa. These compoundsare useful as anticoagulants in treating and preventing cardiovasculardiseases, as anti-inflammatory agents, and as metastasis inhibitors intreating cancer.

BACKGROUND OF THE INVENTION

[0003] Under normal conditions, the coagulation system is naturallybalanced in favor of anticoagulation by a number of proteins circulatingin the blood. These proteins include antithrombin III, a serine-proteaseinhibitor, and protein C, a vitamin-K dependent protein formed in theliver. When injury or trauma occurs, thrombin is produced at preciselevels through an ordered series of reactions. Thrombin is a proteolyticenzyme that occupies a central position in the coagulation process.Thrombin catalyzes the conversion of fibrinogen to fibrin, is a keyeffector enzyme for blood clotting, and is pivotal for other functionsas well, such as activation of helper proteins (including Factors V andVIII and thrombomodulin), and its own activation. Disturbances in thenatural balance between pro- and anti-coagulant forces may result inbleeding or thrombotic diseases.

[0004] A number of coagulation factors present in the blood asprecursors (e.g., Factors VII-XII) lead to the production of thrombin.When the coagulation system is triggered (e.g., when trauma occurs), thecoagulation factors are transformed into activated factors (e.g.,Factors VIIa, IXa, Xa, XIa, etc.) When Factor VII is activated, it formsa complex with tissue factor, a membrane protein. Thus, Factor VIIa ispresent as a complex bound to tissue factor. When triggered, thecoagulation factors and tissue factor complexes undergo an ordered chainof reactions that ultimately lead to conversion of Factor X to FactorXa, and Factor Xa catalyzes the conversion of prothrombin to thrombin.

[0005] An elevated plasma level of coagulation factors, particularlyFactor VIIa, is a risk factor for fatal myocardial infarction andassociated with coronary artery disease and other abnormalities of thecoagulation system, e.g., thrombosis, ischemic vascular disease,intravascular clotting, stroke, embolisms, and so forth. Accordingly,antithrombotic agents have been researched and developed for use intreating cardiovascular and other diseases. Presently establishedantithrombotic agents include heparin, coumarin, and aspirin. There are,however, limitations with these agents. For example, both heparin andcoumarin have a highly-variable dose-related response, and theiranticoagulant effects must be closely monitored to avoid a risk ofserious bleeding. The erratic anticoagulant response of heparin islikely due to its propensity to bind non-specifically to plasmaproteins. Aspirin has a limited efficacy and at high doses presents arisk of gastrointestinal bleeding. Thrombin inhibitors and theirdrawbacks are further discussed in WO 96/20689.

[0006] As may be appreciated, those in the field of pharmaceuticalresearch continue to seek new compounds and compositions havingincreased effectiveness and bioavailability and/or having fewer sideeffects. There is particularly an interest in developing agents that canselectively and directly inhibit key factors in the complicatedcoagulation process. Compounds effective in inhibiting Factors VIIa, Xa,as well as tryptase and urokinase are described in U.S. Pat. Nos.6,335,324 and 6,642,252. Factor VIIa inhibitors are also disclosed inU.S. Pat. No. 6,358,960 and WO 01/44172. U.S. Pat. No. 6,194,409discloses certain bicyclic groups such as isoquinoline groups whichreportedly are advantageous for promoting pharmacological properties.Phenyl glycine derivatives useful as serine protease inhibitors aredisclosed in U.S. Pat. Nos. 6,140,353, 6,242,644, WO 01/90051 and WO03/66588 and U.S. Pat. No. 6,472,393.

[0007] The patents, patent applications, and articles cited above areincorporated herein by reference.

SUMMARY OF THE INVENTION

[0008] Accordingly, the present invention provides novel compoundsaccording to formula (I):

[0009] which are useful as selective inhibitors of serine proteaseenzymes, especially factor VIIa, or a stereoisomer or apharmaceutically-acceptable salt, hydrate, or prodrug thereof, wherein:

[0010] X is —OH, —O(alkyl), —O(aryl), —O(arylalkyl), —NR₅(aryl), or—NR₅(arylalkyl); wherein said aryl or arylalkyl are optionallysubstituted with one to two R₂₅;

[0011] W is hydrogen or —(CR₇R₈)_(q)—H;

[0012] Z is a 5-membered heteroaryl group optionally substituted with1-3 R₉, a five to six membered heterocyclo or cycloalkyl groupoptionally substituted with 1-3 R₉, a 9 to 10 membered bicyclic aryl orheteroaryl optionally substituted with 1-3 substituents selected from R₉and/or R₁₀, or

[0013] Z₁, Z₂ and Z₃ are independently N or CR₉;

[0014] R₁, R₂ and R₃ are attached to any available carbon atom of phenylring A and are independently selected from hydrogen, halogen, cyano,nitro, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, substituted C₁₋₁₀alkyl, substitutedC₂₋₁₀alkenyl, —C(═O)NR I₂R₁₃, —OR₁₂, —CO₂R₁₂, —C(═O)R₁₂, —SR₁₂,—S(O)_(t)R₁₅, —NR₁₂R₁₃, —NR₁₂SO₂R₁₅, —NR₁₄SO₂NR₁₂R₁₃, —NR₁₂CO₂R₁₃,—NR₁₂C(═O)R₁₃, —NR₁₄C(═O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, aryl, heteroaryl,cycloalkyl, and heterocyclo;

[0015] R₅ is hydrogen, C₁₋₄alkyl, NH₂, C₁₋₄alkylamino, hydroxy, orC₁₋₄alkoxy;

[0016] R₇ and R₈ are independently selected from hydrogen, —OR₁₈,—NR₁₈R₁₉, —NR₁₈SO₂R₂₀, alkyl, alkenyl, substituted alkyl, substitutedalkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, alkylthio,—C(═O)H, acyl, —CO₂H, alkoxycarbonyl, sulfonamido, sulfonyl, and phenylin turn optionally substituted with 1-3 of halogen, cyano, haloalkyl,haloalkoxy, nitro, hydroxy, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,amino, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, and/or C₁₋₄aminoalkyl;

[0017] R₉, R₁₀ and R₁₁ are independently selected from hydrogen,halogen, alkyl, substituted alkyl, haloalkyl, haloalkoxy, cyano, nitro,—S(O)_(u)R₂₁, —NR₂₂SO₂R₂₁, —C(═O)NR₂₂R₂₃, —OR₂₂, —CO₂R₂₂, —C(═O)R₂₂,—SR₂₂, —NR₂₂R₂₃, —NR₂₂CO₂R₂₃, —NR₂₂C(═O)R₂₃, —NR₂₂C(═O)NR₂₃R₂₄,—SO₂NR₂₂R₂₃, —NR₂₂SO₂NR₂₃R₂₄, —C(═NR₂₂)NR₂₃R₂₄, five or six memberedheterocyclo or heteroaryl, phenyl, and C₃₋₇cycloalkyl, provided that R₁₁is not —C(═NR₂₂)NR₂₃R₂₄ when W is hydrogen; wherein when R₉, R₁₀ or R₁₁is selected from heterocyclo, heteroaryl, phenyl, and C₃₋₇cycloalkyl,each of said cyclic groups in turn is optionally substituted with up tothree of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄ hydroxyalkyl, C₁₋₄ aminoalkyl,halogen, hydroxy, haloalkyl, haloalkoxy, amino, C₁₋₄ alkylamino, and/orcyano;

[0018] R₁₂, R₁₃, R₁₄, R₁₈, R₁₉, R₂₂ R₂₃, and R₂₄ are independentlyselected from hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;

[0019] R₁₅, R₂₀ and R₂₁ are independently selected from alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,cycloalkyl, and heterocyclo;

[0020] R₂₅ at each occurrence is selected from hydrogen, halogen, cyano,nitro, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, substituted C₁₋₁₀alkyl, substitutedC₂₋₁₀alkenyl, —C(═O)NR₁₂R₁₃, —OR₁₂, —CO₂R₁₂, —C(═O)R₁₂, —SR₁₂,—S(O)_(t)R₁₅, —NR₁₂R₁₃, —NR₁₂SO₂R₁₅, —NR₁₄SO₂NR₁₂R₁₃, —NR₁₂CO₂R₁₃,—NR₁₂C(═O)R₁₃, —NR₁₄C(═O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, aryl, heteroaryl,cycloalkyl, and heterocyclo;

[0021] p is 1 or 2;

[0022] q is 1, 2 or 3;

[0023] t is 1 or 2; and

[0024] u is 1 or 2;

[0025] provided that when Z is phenyl, pyridyl or pyridazinyl, R₉, R₁₀and/or R₁₁ are other than cyano or —C(═NR₂₂)NR₂₃R₂₄.

[0026] The invention also relates to pharmaceutical compositionscontaining at least one compound of formula (I) and apharmaceutically-acceptable carrier or diluent, for use in treatingserine protease or Factor VIIa-associated diseases. Also included withinthe invention are methods of treating such diseases comprisingadministering to a mammal in need of such treatment an effective amountof at least one compound of formula (I). Further included in theinvention are compositions for use as anticoagulants during thepreparation, use, storage, or fractionation of blood and methods ofmaintaining blood in the fluid phase during its preparation, use,storage or fractionation.

DETAILED DESCRIPTION OF THE INVENTION

[0027] The compounds herein described may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms or by synthesis from optically activestarting materials. Many geometric isomers of olefins, C═N double bonds,and the like can also be present in the compounds described herein, andall such stable isomers are contemplated in the present invention. Cisand trans geometric isomers of the compounds of the present inventionare described and may be isolated as a mixture of isomers or asseparated isomeric forms. All chiral, diastereomeric, racemic forms andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. All tautomers of shown or described compounds are alsoconsidered to be part of the present invention.

[0028] The following are definitions of terms used in thisspecification. The initial definition provided for a group or termherein applies to that group or term throughout the presentspecification, individually or as part of another group, unlessotherwise indicated.

[0029] Preferably, the molecular weight of compounds of the presentinvention is less than about 500, 550, 600, 650, 700, 750, or 800 gramsper mole. Preferably, the molecular weight is less than about 800 gramsper mole. More preferably, the molecular weight is less than about 750grams per mole. Even more preferably, the molecular weight is less thanabout 700 grams per mole.

[0030] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Ringdouble bonds, as used herein, are double bonds that are formed betweentwo adjacent ring atoms (e.g., C═C, C═N, or N═N). The present invention,in general, does not cover groups such as N-halo, S(O)H, and SO₂H.

[0031] The present invention is intended to include all isotopes ofatoms occurring in the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0032] In cases wherein there are nitrogen atoms (e.g., amines) oncompounds of the present invention, these can be converted to N-oxidesby treatment with an oxidizing agent (e.g., MCPBA and/or hydrogenperoxides) to afford other compounds of this invention. Thus, all shownand claimed nitrogen atoms are considered to cover both the shownnitrogen and its N-oxide (N→O) derivative.

[0033] The term “alkyl” refers to straight or branched chain hydrocarbongroups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, aremost preferred. When numbers appear in a subscript after the symbol “C”,the subscript defines with more specificity the number of carbon atomsthat a particular group may contain. For example, “C₁₋₆alkyl” refers tostraight and branched chain alkyl groups with one to six carbon atoms,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl,and so forth. When the subscript “0” is used, as in C₀, this refers to abond. Thus, the term C₀₋₂hydroxyalkyl refers to hydroxy, hydroxymethyl,and hydroxyethyl.

[0034] The term “substituted alkyl” refers to an alkyl group as definedabove having one, two, or three substituents selected from the groupconsisting of halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano,keto (═O), haloalkoxy, —OR, —SR, —NRR′, —NRSO₂, —NRSO₂R′, —SO₂R″,—SO₂NRR′, —CO₂R, —C(═O)R, —C(═O)NRR′, —OC(═O)R, —OC(═O)NRR′, —NRC(═O)R′,—NRCO₂R′, ═N—OH, ═N—O-alkyl, aryl, heteroaryl, heterocyclo andcycloalkyl, wherein R and R′ are selected from hydrogen, alkyl, alkenyl,amino, alkylamino, substituted alkylamino, benzyl, phenylethyl,cycloalkyl, heterocyclo, aryl, and heteroaryl, or R and R′ together mayform a heterocyclo or heteroaryl ring, and R″ is alkyl, alkenyl, benzyl,phenylethyl, cycloalkyl, heterocyclo, aryl, and/or heteroaryl. When analkyl is substituted with an aryl, heteroaryl, heterocyclo orcycloalkyl, those groups are as recited below and thus optionally may besubstituted as recited below. Each of R, R′, and R″ in turn may havezero to three substituents (preferably 0-2 substituents), appropriatelyselected from R′″, C₁₋₄ alkyl, and C₁₋₄alkyl substituted with R′″,wherein R′″ is selected from halogen, haloalkyl, C₂₋₅alkenyl, nitro,cyano, —OH, —O(C₁₋₄alkyl), haloalkoxy, phenyl, benzyl, phenylethyl,phenyloxy, benzyloxy, —SH, —S(C₁₋₄alkyl), —S(phenyl), —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —NH(cycloalkyl), —NHSO₂,—NHSO₂(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄alkyl),—SO₂N(C₁₋₄alkyl)₂, —CO₂H, —CO₂(C₁₋₄alkyl), —C(═O)H, —C(═O)C₁₋₄alkyl,—C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, —OC(═O)C₁₋₄alkyl,—OC(═O)NH₂, —OC(═O)NH(C₁₋₄alkyl), —OC(═O)N(C₁₋₄alkyl)₂,—NHC(═O)C₁₋₄alkyl, —NHCO₂(C₁₋₄alkyl), C₃₋₇cycloalkyl, C₅₋₆heteoraryl,and C₄₋₇heterocyclo.

[0035] When the term alkyl is used as a suffix with a second namedgroup, as in arylalkyl or cycloalkylalkyl, this refers to a substitutedalkyl in which at least one of the substituents is the second namedgroup. For example, the term arylalkyl includes benzyl and any otherstraight or branched chain alkyl having at least one aryl group attachedat any point of the alkyl chain. Other substituents may be attached tothe alkyl chain or the second named group. Such substituents may beselected as appropriate from the groups recited above in the definitionof substituted alkyl and/or from those recited herein for the secondnamed group.

[0036] The term “alkenyl” refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and at least one doublebond. Alkenyl groups of 2 to 6 carbon atoms and having one double bondare most preferred.

[0037] The term “alkynyl” refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and at least one triplebond. Alkynyl groups of 2 to 6 carbon atoms and having one triple bondare most preferred.

[0038] The term “alkylene” refers to bivalent straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms, e.g., {—CH₂—}n, wherein n is 1 to 12, preferably 1-8. Loweralkylene groups, that is, alkylene groups of 1 to 4 carbon atoms, aremost preferred. The terms “alkenylene” and “alkynylene” refer tobivalent radicals of alkenyl and alknyl groups, respectively, as definedabove.

[0039] When reference is made to a substituted alkylene, alkenylene, oralkynylene, these groups are substituted with one to three substitutentsas defined above for alkyl groups. A substituted alkylene, alkenylene,or alkynylene may have a ringed substituent attached in a spiro fashionas in

[0040] and so forth.

[0041] The term “alkoxy” refers to the group —OR, wherein R is alkyl oralkenyl. The term “alkylthio” refers to the group —SR, wherein R isalkyl or alkenyl. The term “alkylamino” refers to the group —NR′R″,wherein each of R′ and R″ is selected from hydrogen, alkyl, alkenyl,cycloalkyl, aryl, heteroaryl, or heterocyclo, as defined herein,provided that both R′ and R″ are not hydrogen. The term “amino” refersto —NH₂. A substituted alkoxy, alkythio, or alkylamino may have zero tothree substituents as defined above for substituted alkyl.

[0042] When a subscript is used with an alkoxy, alkylthio or alkylamino,the subscript refers to the number of carbon atoms that the group maycontain in addition to heteroatoms. Thus, for example, monovalentC₁₋₂alkylamino includes the groups —NHCH₃, —NHCH₂CH₃, and —N(CH₃)₂. Alower alkylamino comprises an alkylamino having one to four carbonatoms.

[0043] The alkoxy, alkylthio, or alkylamino groups may be monovalent orbivalent. By “monovalent” it is meant that the group has a valency(i.e., power to combine with another group), of one, and by “bivalent”it is meant that the group has a valency of two. For example, amonovalent alkoxy includes groups such as —O—C₁₋₁₂alkyl, whereas abivalent alkoxy includes groups such as —O—C₁₋₁₂alkylene-, etc.

[0044] The term “acyl” refers to a carbonyl {—C(═O)—} linked to anorganic group i.e.,

[0045] wherein R may be selected from alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, heterocyclo, cycloalkyl, and heteroaryl, asdefined herein.

[0046] The term “alkoxycarbonyl” refers to a carboxy or ester group{—CO₂—} linked to an organic radical, i.e.,

[0047] wherein R is as defined for acyl. “Carboxy” refers to the groupCO₂H, and “carboxyalkyl” refers to —R—CO₂H, wherein R is alkylene orsubstituted alkylene.

[0048] The term “carbamyl” refers to a functional group in which anitrogen atom is directly bonded to a carbonyl, i.e., as in —NRC(═O)R′or —C(═O)NRR′, wherein R and R′ can be hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkoxy, cycloalkyl, aryl,heterocyclo, or heteroaryl.

[0049] The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

[0050] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo, and iodo; and “counterion” is used to represent a small,negatively charged species such as chloride, bromide, hydroxide,acetate, and sulfate.

[0051] The term “haloalkyl” means an alkyl having one or more halosubstituents and thus includes, for example, trifluoromethyl.

[0052] The term “perfluoroalkyl” means an alkyl group having from one tofive fluoro atoms, such as pentafluoroethyl. The term “perfluoromethyl”means a methyl group substituted by one, two, or three fluoro atoms,i.e., —CH₂F, —CHF₂ and CF₃.

[0053] The term “haloalkoxy” means an alkoxy group having one or morehalo substituents. For example, “haloalkoxy” includes —OCF₃.

[0054] The term “sulfonyl” refers to a sulphoxide group (i.e., —S(O)13)linked to an organic radical R″, wherein R″ is alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, heterocyclo, heteroaryl, oraryl. Sulfonic acid is —SO₃H.

[0055] The term “sulfonamide” or “sulfonamido” refers to the group—S(O)₂NRR′, wherein R and R′ are selected from hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,heterocyclo, heteroaryl and aryl. Preferably when one of R and R′ isoptionally substituted cycloalkyl, heterocyclo, heteroaryl or aryl (asdefined below), the other of R and R′ is hydrogen or alkyl.

[0056] The term “cycloalkyl” refers to fully saturated and partiallyunsaturated substituted or unsubstituted hydrocarbon rings of 3 to 9,preferably 3 to 7 carbon atoms. When substituted, the cycloalkyl willcontain one to three (preferably one to two) groups selected from thegroup consisting of C₀₋₆alkyl optionally substituted with (or linked to)one to two of halogen, perfluoroalkyl, alkenyl, alkynyl, nitro, cyano,keto (═O), haloalkoxy, —OR, —SR, —NRR′, —NRSO₂, —NRSO₂R′, —SO₂R″,—SO₂NRR′, —CO₂R, —C(═O)R, —C(═O)NRR′, —OC(═O)R, —OC(═O)NRR′, —NRC(═O)R′,—NRCO₂R′, ═N—OH, ═N—O-alkyl, phenyl, 3 to 6 membered heteroaryl orheterocyclo, and/or C₃₋₇cycloalkyl, wherein R and R′ are independentlyselected from hydrogen, alkyl, alkenyl, phenyl, benzyl, phenylethyl,C₃₋₇cycloalkyl, and 3 to 6 membered heterocyclo or heteroaryl, and R″ isalkyl, alkenyl, phenyl, benzyl, phenylethyl, C₃₋₇cycloalkyl, and/or 3 to6 membered heterocyclo or heteroaryl. The term “cycloalkyl” alsoincludes such rings having a phenyl ring fused thereto or having acarbon-carbon bridge of 3 to 4 carbon atoms. Additionally, each of R, R′and R″ in turn may, as appropriate, be optionally substituted with oneto two C₀₋₄alkyl optionally substituted with (or linked to) one to twoof halogen, CF₃, OCF₃, alkenyl, nitro, cyano, keto (═O), hydroxy,alkoxy, SH, S(alkyl), NH₂, NH(alkyl), N(alkyl)₂, CO₂H, CO₂(alkyl),C(═O)H, and/or C(═O)alkyl.

[0057] The term “aryl” refers to phenyl and naphthyl, with phenyl beingpreferred. The term “aryl” includes such rings having zero to threesubstituents (preferably 0-2 substituents). When substituted, the arylwill contain one to three C₀₋₆alkyl optionally substituted with (orlinked to) one to two of halogen, perfluoroalkyl, alkenyl, alkynyl,nitro, cyano, haloalkoxy, —OR, —SR, —NRR′, —NRSO₂, —NRSO₂R′, —SO₂R″,—SO₂NRR′, —CO₂R, —C(═O)R, —C(═O)NRR′, —OC(═O)R, —OC(═O)NRR′, —NRC(═O)R′,—NRCO₂R′, phenyl, 3 to 6 membered heteroaryl or heterocyclo, andC₃₋₇cycloalkyl, wherein R and R′ are independently selected fromhydrogen, alkyl, alkenyl, phenyl, benzyl, phenylethyl, C₃₋₇cycloalkyl,or 3 to 6 membered heterocyclo and heteroaryl, and R″ is alkyl, alkenyl,phenyl, benzyl, phenylethyl, C₃₋₇cycloalkyl, and/or 3 to 6 memberedheterocyclo or heteroaryl. Additionally, two substituents attached to anaryl, particularly a phenyl group, may join to form a further ringincluding a spiro ring or a fused ring, e.g., spiro-cyclopentyl or fusedcyclohexenyl, or fused heteroaryl or heterocyclo. Each of R, R′, and R″in turn may, as appropriate, be optionally substituted with one to twoC₀₋₄alkyl optionally substituted with (or linked to) one to two ofhalogen, CF₃, OCF₃, alkenyl, nitro, cyano, keto (═O), hydroxy, alkoxy,SH, S(alkyl), NH₂, NH(alkyl), N(alkyl)₂, CO₂H, CO₂(alkyl), C(═O)H,and/or C(═O)alkyl.

[0058] The term “heterocyclo” refers to substituted and unsubstitutednon-aromatic 3 to 7 membered monocyclic groups, 7 to 11 memberedbicyclic groups, and 10 to 15 membered tricyclic groups, in which atleast one of the rings has at least one heteroatom (O, S or N). Eachring of the heterocyclo group containing a heteroatom can contain one ortwo oxygen or sulfur atoms and/or from one to four nitrogen atoms,provided that the total number of heteroatoms in each ring is four orless, and further provided that the ring contains at least one carbonatom and no two adjacent heteroatoms are simultaneously selected from—O— and —S—. The fused rings completing bicyclic and tricyclic groupsmay contain only carbon atoms and may be saturated, partially saturated,or unsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. The heterocyclogroup may be attached at any available nitrogen or carbon atom. Theheterocyclo ring may contain zero to three substituents (preferably 0-2substituents), selected from C₀₋₆alkyl optionally substituted with (orlinked to) one to two of halogen, perfluoroalkyl, alkenyl, alkynyl,nitro, cyano, haloalkoxy, keto (═O), —OR, —SR, —NRR′, —NRSO₂, —NRSO₂R′,—SO₂R″, —SO₂NRR′, —CO₂R, —C(═O)R, —C(═O)NRR′, —OC(═O)R, —OC(═O)NRR′,—NRC(═O)R′, —NRCO₂R′, phenyl, 3 to 6 membered heteroaryl or heterocyclo,and/or C₃₋₇cycloalkyl, wherein R and R′ are independently selected fromhydrogen, alkyl, alkenyl, phenyl, benzyl, phenylethyl, C₃₋₇cycloalkyl,and 3 to 6 membered heterocyclo or heteroaryl, and R″ is alkyl, alkenyl,phenyl, benzyl, phenylethyl, C₃₋₇cycloalkyl, or 3 to 6 memberedheterocyclo or heteroaryl. The term “heterocyclo” also includes suchrings having a phenyl ring fused thereto or having a carbon-carbonbridge of 3 to 4 carbon atoms. Additionally, each of R, R′ and R″ inturn may, as appropriate, be optionally substituted with one to twoC₀₋₄alkyl optionally substituted with (or linked to) one to two ofhalogen, CF₃, OCF₃, alkenyl, nitro, cyano, keto (═O), hydroxy, alkoxy,SH, S(alkyl), NH₂, NH(alkyl), N(alkyl)₂, CO₂H, CO₂(alkyl), C(═O)H,and/or C(═O)alkyl. Exemplary monocyclic groups include oxiranyl,aziridinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl,tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

[0059] The term “heteroaryl” refers to substituted and unsubstitutedaromatic 5 to 7 membered monocyclic groups, 9 or 10 membered bicyclicgroups, and 11 to 14 membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings. Each ring of theheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms, provided thatthe total number of heteroatoms in each ring is four or less, each ringhas at least one carbon atom, and no two adjacent heteroatoms aresimultaneously selected from —O— and —S—. The fused rings completing thebicyclic and tricyclic groups may contain only carbon atoms and may besaturated, partially saturated, or unsaturated. The nitrogen and sulfuratoms may optionally be oxidized and the nitrogen atoms may optionallybe quaternized. Heteroaryl groups which are bicyclic or tricyclic mustinclude at least one fully aromatic ring, but the other fused ring orrings may be aromatic or non-aromatic. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring. Theheteroaryl ring system may contain zero to three substituents(preferably 0-2 substituents), selected from C₀₋₆alkyl optionallysubstituted with (or linked to) one to two of halogen, perfluoroalkyl,alkenyl, alkynyl, nitro, cyano, haloalkoxy, keto (═O), —OR, —SR, —NRR′,—NRSO₂, —NRSO₂R′, —SO₂R″, —SO₂NRR′, —CO₂R, —C(═O)R, —C(═O)NRR′,—OC(═O)R, —OC(═O)NRR′, —NRC(═O)R′, —NRCO₂R′, phenyl, 3 to 6 memberedheteroaryl or heterocyclo, and/or C₃₋₇cycloalkyl, wherein R and R′ areindependently selected from hydrogen, alkyl, alkenyl, phenyl, benzyl,phenylethyl, C₃₋₇cycloalkyl, and 3 to 6 membered heterocyclo orheteroaryl, and R″ is alkyl, alkenyl, phenyl, benzyl, phenylethyl,C₃₋₇cycloalkyl, and/or 3 to 6 membered heterocyclo or heteroaryl.Additionally, each of R, R′ and R″ in turn may, as appropriate, beoptionally substituted with one to two C₀₋₄alkyl optionally substitutedwith (or linked to) one to two of halogen, CF₃, OCF₃, alkenyl, nitro,cyano, keto (═O), OH, O(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH₂,NH(alkyl), N(alkyl)₂, CO₂H, CO₂(alkyl), C(═O)H, and/or C(═O)alkyl.

[0060] Exemplary monocyclic heteroaryl groups include pyrrolyl,pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

[0061] Exemplary bicyclic heteroaryl groups include indolyl, indazolyl,benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl,dihydroisoindolyl, benzothiadiazolyl, phthalazinyl, benzotriazinyl,quinazolinyl, quinolinyl, benzoxazolyl, benzothiopheneyl,tetrahydrophthalazinyl, tetrahydroquinolinyl, tetrahydroquinazolinyl,tetrahydrocinnolinyl, tetrahydroquinoxalinyl and the like.

[0062] Exemplary tricyclic heteroaryl groups include carbazolyl,benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl andthe like.

[0063] The term “carbocyclic” means a saturated or unsaturatedmonocyclic or bicyclic ring in which all atoms of all rings are carbon.Thus, the term includes cycloalkyl and aryl rings. The carbocyclic ringmay be substituted in which case the substituents are selected fromthose recited above for cycloalkyl and aryl groups, as appropriate.

[0064] When the term “unsaturated” is used herein to refer to a ring orgroup, the ring or group may be fully unsaturated or partiallyunsaturated.

[0065] Throughout the specification, groups and substituents thereof maybe chosen by one skilled in the field to provide stable moieties andcompounds. The terms “appropriately selected” are “appropriatelysubstituted” as used herein are intended to mean that one skilled in thefield would make selections from the recited groups to provide stablemoieties and compounds.

[0066] The compounds of of the present inventions form salts which arealso within the scope of this invention. Reference to a compound of theformula I herein is understood to include reference to salts thereof,unless otherwise indicated. The term “salt(s)”, as employed herein,denotes acidic and/or basic salts formed with inorganic and/or organicacids and bases. In addition, when a compound of formula I contains botha basic moiety, such as, but not limited to an amine or a pyridine ring,and an acidic moiety, such as, but not limited to, a carboxylic acid,zwitterions (“inner salts”) may be formed and are included within theterm “salt(s)” as used herein. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also useful, e.g., in isolation or purification stepswhich may be employed during preparation. Salts of the compounds of theformula I may be formed, for example, by reacting a compound of theformula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

[0067] Exemplary acid addition salts include acetates (such as thoseformed with acetic acid or trihaloacetic acid, for example,trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

[0068] Exemplary basic salts include ammonium salts, alkali metal saltssuch as sodium, lithium, and potassium salts, alkaline earth metal saltssuch as calcium and magnesium salts, salts with organic bases (forexample, organic amines) such as benzathines, dicyclohexylamines,hydrabamines [formed with N,N-bis(dehydro-abietyl)ethylenediamine],N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quaternized with agents such as loweralkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g., benzyl and phenethyl bromides), and others.

[0069] Compounds of the present invention, and salts thereof, may existin their tautomeric form, in which hydrogen atoms are transposed toother parts of the molecules and the chemical bonds between the atoms ofthe molecules are consequently rearranged. It should be understood thatall tautomeric forms, insofar as they may exist, are included within theinvention. Additionally, inventive compounds may have trans and cisisomers and may contain one or more chiral centers, therefore existingin enantiomeric and diastereomeric forms. The invention includes allsuch isomers, as well as mixtures of cis and trans isomers, mixtures ofdiastereomers and racemic mixtures of enantiomers (optical isomers).When no specific mention is made of the configuration (cis, trans or Ror S) of a compound (or of an asymmetric carbon), then any one of theisomers or a mixture of more than one isomer is intended. The processesfor preparation can use racemates, enantiomers, or diastereomers asstarting materials. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods, for example, bychromatographic or fractional crystallization. The inventive compoundsmay be in the free or hydrate form.

[0070] Compounds of the present invention are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% compound ofthe present invention (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds arealso contemplated herein as part of the present invention.

[0071] “Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that there presentlyrecited compounds do not contain a N-halo, S(O)₂H, or S(O)H group.

[0072] In addition, compounds of formula I may have prodrug forms. Anycompound that will be converted in vivo to provide the bioactive agent(i.e., a compound of formula I) is a prodrug within the scope and spiritof the invention. Various forms of prodrugs are well known in the art.For examples of such prodrug derivatives, see:

[0073] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985),and Methods in Enzymology, Vol. 42, at pp. 309-396, edited by K. Widder,et. al. (Academic Press, 1985);

[0074] b) A Textbook of Drug Design and Development, edited byKrosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application ofProdrugs,” by H. Bundgaard, at pp. 113-191 (1991);

[0075] c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38(1992);

[0076] d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol.77, p. 285 (1988); and

[0077] e) N. Kakeya, et. al., Chem Phar Bull., Vol. 32, p. 692 (1984).

[0078] Compounds containing a carboxy group can form physiologicallyhydrolyzable esters which serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g.methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl andother well known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters may be prepared byconventional techniques known in the art.

[0079] It should further be understood that solvates (e.g., hydrates) ofthe compounds of the present invention are also with the scope of thepresent invention. Methods of solvation are generally known in the art.

[0080] As used herein, “treating” or “treatment” cover the treatment ofa disease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

[0081] “Therapeutically effective amount” is intended to include anamount of a compound of the present invention that is effective whenadministered alone or in combination to inhibit factor VIIa.“Therapeutically effective amount” is also intended to include an amountof the combination of compounds claimed that is effective to inhibitfactor VIIa. The combination of compounds is preferably a synergisticcombination. Synergy, as described, for example, by Chou and Talalay,Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect (in this case,inhibition of factor VIIa) of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedantithrombotic effect, or some other beneficial effect of thecombination compared with the individual components.

PREFERRED EMBODIMENTS

[0082] In a preferred embodiment, the present invention providescompounds of formula (Ia):

[0083] or a stereoisomer or a pharmaceutically-acceptable salt, hydrateor prodrug thereof, wherein:

[0084] X is —OH, —O(phenyl) optionally substituted with one to two R₂₅,—O(benzyl) optionally substituted with one to two R₂₅, —NH(phenyl)optionally substituted with one to two R₂₅, or —NH(benzyl) optionallysubstituted with one to two R₂₅;

[0085] W is hydrogen or —(CH₂)_(q)—H;

[0086] Z is selected from a 5-membered heteroaryl group optionallysubstituted with 1-3 R₉, a five to six membered heterocyclo orcycloalkyl group optionally substituted with 1-3 R₉, a 9 to 10 memberedbicyclic aryl or heteroaryl optionally substituted with 1-3 substituentsselected from R₉ and/or R₁₀, and

[0087] Z₁, Z₂ and Z₃ are independently N or CR₉ and at least one of Z₁,Z₂ and Z₃ is N;

[0088] R₁ and R₂ are independently selected from hydrogen, halogen,cyano, nitro, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, substituted C₁₋₁₀alkyl,substituted C₂₋₁₀alkenyl, —C(═O)NR₁₂R₁₃, —OR₁₂, —CO₂R₁₂, —C(═O)R₁₂,—SR₁₂, —S(O)_(t)R₁₅, —NR₁₂R₁₃, —NR₁₂SO₂R₁₅, —NR₁₄SO₂NR₁₂R₁₃,—NR₁₂CO₂R₁₃, —NR₁₂C(═O)R₁₃—NR₁₄C(═O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, aryl,heteroaryl, cycloalkyl, and heterocyclo;

[0089] R₉, R₁₀ and R₁₁ are independently selected from hydrogen,halogen, alkyl, substituted alkyl, haloalkyl, haloalkoxy, cyano, nitro,—S(O)_(u)R₂₁, —NR₂₂SO₂R₂₁, —C(═O)NR₂₂R₂₃, —OR₂₂, —CO₂R₂₂, —C(═O)R₂₂,—SR₂₂, —NR₂₂R₂₃, —NR₂₂CO₂R₂₃, —NR₂₂C(═O)R₂₃, —NR₂₂C(═O)NR₂₃R₂₄,—SO₂NR₂₂R₂₃, —NR₂₂SO₂NR₂₃R₂₄, —C(═NR₂₂)NR₂₃R₂₄, five or six memberedheterocyclo or heteroaryl, phenyl, and C₃₋₇cycloalkyl, provided that R₁₁is not —C(═NR₂₂)NR₂₃R₂₄ when W is hydrogen; wherein when R₉, R₁₀ or R₁₁is selected from heterocyclo, heteroaryl, phenyl, and C₃₋₇cycloalkyl,each of said cyclic groups in turn is optionally substituted with up tothree of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄ hydroxyalkyl, C₁₋₄ aminoalkyl,halogen, hydroxy, haloalkyl, haloalkoxy, amino, C₁₋₄ alkylamino, and/orcyano;

[0090] R₁₂, R₁₃, R₁₄, R₁₈, R₁₉, R₂₂ R₂₃, and R₂₄ are independentlyselected from hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;

[0091] R₁₅, R₂₀ and R₂₁ are independently selected from alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,cycloalkyl, and heterocyclo; R₁₆ is alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, heteroaryl, cycloalkyl, or heterocyclo;

[0092] R₂₅ at each occurrence is selected from C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl,haloalkoxy, amino, C₁₋₄alkylamino, and/or cyano;

[0093] p is 1 or 2;

[0094] q is 1, 2 or 3; and

[0095] u is 1 or 2;

[0096] provided that when Z is phenyl, pyridyl or pyridazinyl, R₉, R₁₀and/or R₁₁ are other than cyano or —C(═NR₂₂)NR₂₃R₂₄.

[0097] More preferred compounds are those having the formula (Ia), asrecited above, or a stereoisomer or pharmaceutically-acceptable salts,hydrates, or prodrugs thereof, wherein:

[0098] X is selected from —OH, —O(phenyl), —O(benzyl), —NH(phenyl), andwherein each phenyl or benzyl group is optionally subsituted with one totwo R₂₅,

[0099] W is hydrogen or —(CH₂)_(q)—H;

[0100] Z is selected from

[0101] R₁ and R₂ are OR₁₂;

[0102] R₉ is selected from hydrogen, halogen, alkyl, substituted alkyl,haloalkyl, haloalkoxy, cyano, nitro, —S(O)_(u), R₂₁, —NR₂₂SO₂R₂₁,—C(═O)NR₂₂R₂₃, —OR₂₂, —CO₂R₂₂, —C(═O)R₂₂, —SR₂₂, —NR₂₂R₂₃, —NR₂₂CO₂R₂₃,—NR₂₂C(═O)R₂₃, —NR₂₂C(═O)NR₂₃R₂₄, —SO₂NR₂₂R₂₃, —NR₂₂SO₂NR₂₃R₂₄, five orsix membered heterocyclo or heteroaryl, phenyl, and C₃₋₇cycloalkyl;

[0103] R₁₂, R₂₂, R₂₃ and R₂₄ are selected from hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,cycloalkyl, or heterocyclo;

[0104] R₂₁ is selected from alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;

[0105] R₂₅ at each occurrence is selected from C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl,haloalkoxy, amino, C₁₋₄alkylamino, and/or cyano;

[0106] q is 1, 2 or 3;

[0107] s is 0, 1, or 2; and

[0108] u is 1 or 2;

[0109] provided that when Z is phenyl, R₉ and/or R₁₁ are other thancyano or —C(═NR₂₂)NR₂₃R₂₄.

[0110] More preferred are compounds having the formula (Ib),

[0111] or a stereoisomer or pharmaceutically-acceptable salts, hydrates,or prodrugs thereof, wherein:

[0112] X is selected from —O(phenyl), —O(benzyl), and —NH(phenyl)—NH(benzyl), wherein each group X is optionally subsituted with one totwo R₂₅,

[0113] W is hydrogen or —(CH₂)_(q)—H;

[0114] Z is selected from

[0115]  R₉ is independently

[0116] selected from hydrogen, halogen, alkyl, aminoalkyl, hydroxyalkyl,haloalkyl, haloalkoxy, alkoxy, cyano, nitro, alkylamino, alkylthio,thioalkyl, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, five orsix membered heterocyclo or heteroaryl, phenyl, and C₃₋₇cycloalkyl;

[0117] R_(12a) and R_(12b) are independently selected from hydrogen,alkyl, substituted alkyl, phenyl, and benzyl;

[0118] R₂₅ at each occurrence is selected from C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl,haloalkoxy, amino, C₁₋₄alkylamino, and/or cyano;

[0119] p is 1 or 2; and

[0120] s is 0, 1 or 2;

[0121] provided that when Z is phenyl, R₉ and/or R₁₁ are other thancyano or —C(═NR₂₂)NR₂₃R₂₄.

[0122] More preferred are compounds as immediately defined abovewherein:

[0123] R_(12a) and R_(12b) are selected from C₁₋₄alkyl; and

[0124] Z is selected from:

[0125] More preferred compounds are those having the formula (I),wherein:

[0126] Z is selected from:

[0127] Z₄ is fused to ring A comprising the common carbon atom C* and is

[0128] Z₅ is fused to ring A comprising the common carbon atom C* and isselected from:

[0129] Z₆ is fused to ring A comprising the common carbon atom C* and is

[0130] Z₇ is fused to ring A comprising the common carbon atom C* and isselected from:

[0131] Z₈ is fused to ring B comprising the common nitrogen atom N* andis selected from

[0132] Z₉ is CH or N;

[0133] r is 0, 1, or 2; and

[0134] s is 0, 1, 2, or 3.

[0135] More preferred compounds are those having the formula (I),wherein:

[0136] Z is selected from:

[0137] More preferred compounds are those having the formula (I),wherein:

[0138] R₁ and R₂ are OR₁₂.

[0139] More preferred compounds are those having the formula (I),wherein:

[0140] wherein R₁₂ is C₁₋₆alkyl, phenyl, or benzyl optionallysubstituted with one to two of halogen, cyano, haloalkyl, haloalkoxy,nitro, hydroxy, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, amino,NH(C₁₋₄alkyl), and N(C₁₋₄alkyl)₂.

[0141] More preferred compounds are those having the formula (I),wherein:

[0142] wherein W is hydrogen.

[0143] More preferred compounds are those having the formula (I),wherein:

[0144] X is NH(phenyl), NH(benzyl), SO₂alkyl, or SO₂(phenyl) optionallysubstituted with one to two of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl, haloalkoxy, amino,C₁₋₄alkylamino, and/or cyano.

[0145] More preferred compounds are those having the formula (Ib),wherein:

[0146] X is selected from —O(phenyl) optionally substituted with one totwo R₂₅, —O(benzyl) optionally substituted with one to two R₂₅,—NH(phenyl) optionally substituted with one to two R₂₅, and—NH(phenylalkyl) optionally substituted with one to two R₂₅;

[0147] W is hydrogen or —(CH₂)_(q)—H;

[0148] Z is selected from:

[0149] Z₁, Z₂ and Z₃ are selected from N and CR₉;

[0150] Z₄ is fused to ring A comprising the common carbon atom C* and is

[0151] Z₅ is fused to ring A comprising the common carbon atom C* and isselected from:

[0152] Z₆ is fused to ring A comprising the common carbon atom C* and is

[0153] Z₇ is fused to ring A comprising the common carbon atom C* and isselected from:

[0154] Z₈ is fused to ring B comprising the common nitrogen atom N* andis selected from

[0155] Z₉ is CH or N;

[0156] R₉ and R₁₀ are independently selected from hydrogen, halogen,alkyl, substituted alkyl, haloalkyl, haloalkoxy, cyano, nitro,—S(O)_(u), R₂₁, —NR₂₂SO₂R₂₁, —C(═O)NR₂₂R₂₃, —OR₂₂, —CO₂R₂₂, —C(═O)R₂₂,—SR₂₂, —NR₂₂R₂₃, —NR₂₂CO₂R₂₃, —NR₂₂C(═O)R₂₃, —NR₂₂C(═O)NR₂₃R₂₄,—SO₂NR₂₂R₂₃, —NR₂₂SO₂NR₂₃R₂₄, —C(═NR₂₂)NR₂₃R₂₄, five or six memberedheterocyclo or heteroaryl, phenyl, and C₃₋₇cycloalkyl, provided that R₉and R₁₀ are not —C(═NR₂₂)NR₂₃R₂₄ when W is hydrogen; wherein when R₉ orR₁₀ is independently selected from heterocyclo, heteroaryl, phenyl, andC₃₋₇cycloalkyl, each of said cyclic groups in turn is optionallysubstituted with up to three of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl, haloalkoxy, amino,C₁₋₄alkylamino, and/or cyano;

[0157] R₁₂, R_(12a), R_(12b), R₂₂ R₂₃, and R₂₄ are independentlyselected from hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;

[0158] R₂₁ is selected from alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;

[0159] R₂₅ at each occurrence is selected from C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl,haloalkoxy, amino, C₁₋₄alkylamino, and/or cyano;

[0160] p is 1 or 2;

[0161] q is 1, 2 or 3;

[0162] r is 0, 1, or 2;

[0163] s is 0, 1, 2, or 3;

[0164] t is 1 or 2; and

[0165] u is 1 or 2.

[0166] More preferred compounds are those having the formula (I),wherein:

[0167] X is NR₅(benzyl) optionally substituted with one to two R₂₅;

[0168] W is hydrogen;

[0169] Z is

[0170] and

[0171] R₂₅ at each occurrence is selected from halogen, cyano, nitro,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, substituted C₁₋₁₀alkyl, substitutedC₂₋₁₀alkenyl, —C(═O)NR₁₂R₁₃, —OR₁₂, —CO₂R₁₂, —C(═O)R₁₂, —SR₁₂,—S(O)_(t)R₁₅, —NR₁₂R₁₃, —NR₁₂SO₂R₁₅, —NR₁₄SO₂NR₁₂R₁₃, —NR₁₂CO₂R₁₃,—NR₁₂C(═O)R₁₃, —NR₁₄C(═O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, aryl, heteroaryl,cycloalkyl, and heterocyclo.

[0172] More preferred compounds are those having the formula (I),wherein:

[0173] Z is

[0174] More preferred compounds are those having the formula (I),wherein:

[0175] More preferred compounds are those having the formula (I),wherein:

[0176] X is OH;

[0177] W is hydrogen; and

[0178] Z is

[0179] Methods of Preparation

[0180] The compounds of the invention may be prepared by the exemplaryprocesses described in the following Schemes A through G.

[0181] Compounds 2 [or compounds of formula (Ia)] can be prepared byreduction of the corresponding nitrile 1 using hydrogen and a catalystsuch as Raney Nickel or Pd/C. The preparation of compounds 1 isdescribed in U.S. Pat. No. 6,472,393.

[0182] Compounds 4 are typically final products of formula (Ia).Compounds 4 were obtained by deprotection of a basic functionality incompound 3. Typical protecting group for a basic functionality aredescribed in Green and Wuts, “Protective Groups in Organic Synthesis,Second Edition,” John Wiley and Sons Eds, New York, (1991). Protectinggroup for amino or anilino groups include tert-butylcarbamate (Boc)which can be removed with a solution of TFA in DCM. Another protectinggroup for an amino or anilino group is 2,4-dimethoxybenzyl which can beremoved by treatment with TFA in anisole or by catalytic hydrogenation.In the case of a primary amine or aniline, the nitrogen can be protectedwith one or two 2,4-dimethoxybenzyl groups. The first group can beremoved with dilute TFA in an organic solvent while the secondprotecting can be removed with a 10-50% solution of TFA in anisole.Preparation of compounds of formula 3 is described in Schemes C-F.

[0183] Amides 6 can be prepared from the corresponding carboxylic acids5 by treatment with an amine and a coupling reagent. Coupling conditionscan be found in Bodanszky, “Principles of Peptide Synthesis, SecondEdition” Springer Verlag Ed, Berlin (1993). Coupling reagents includeCDI, DIC, and EDC. Optionally, an intermediate activated ester can beprepared by adding one equivalent of 1-hydroxybenzotriazole or1-hydroxy-7-azabenzotriazole. Other coupling reagents include HATU,HBTU, and Py-Brop which are usually reacted in presence of oneequivalent of a tertiary base such as DIEA or TEA.

[0184] Compounds 10 and 10b can be prepared by a condensation reactionas described in U.S. Pat. No. 6,472,393. Reaction of an amine 7, with analdehyde 8 and an isonitrile 9 in presence of a Lewis acid and an alkylalcohol affords condensation product 10 after hydrolysis. Suitable Lewisacid catalysts include boron-trifluoride etherate or aluminiumtrichloride. Suitable alkyl alcohols include MeOH, EtOH, and I-PrOH.Examples of isonitrile 9 include benzyl isocyanide and tosylmethylisocyanide. In some cases amides 10b were obtained as a side product inthe reaction. These could be separated by column chromatography.

[0185] Alternatively to Scheme D, ester 10 can be prepared fromhydroxy-ester 12. Compounds 12 can be prepared through a Strecker typesynthesis, by condensation of an aldehyde 11 with trimethylsilylcyanidein presence of a Lewis acid catalyst such as Boron trifluoride etherate,followed by treatment with hydrochloric acid in MeOH and hydrolysis.Optionally, methyl ester 10 may be converted to the benzyl ester viasaponification, followed by alkylation with benzyl bromide. Compounds 12can be converted to 13 through one of the many halogenation methodsknown in the art. One suitable method is to treat the alcohol with asolution of bromine, triphenylphosphine and imidazole.Triphenylphosphine can be replaced with polystyrene boundtriphenylphosphine which facilitates isolation of 13. Chlorination ofcompound 13 may be accomplished by treatment with methansulfonylchloride and triethylamine in DCM. The halide 13 can be converted to 10by nucleophilic substitution with an amine or aniline in an organicsolvent such as DCM and in presence of a base such as TEA or DIPEA.

[0186] Saponification of methyl ester 10 to the corresponding carboxylicacids 5 can be accomplished using standard conditions well know in theart such as treatment with aqueous lithium hydroxide. Conversion ofbenzyl ester 10 to the carboxylic acids 5 can be accomplished viacatalytic hydrogenation.

[0187] Scheme G described the preparation of reagent 20 (PG-Z-NH₂ whereZ =1-aminoisoquinoline and PG=bis(2,4-dimethoxybenzyl) which can be usedto make compounds of formula (I) by the methods described in SchemesA-F. Compound 15 was prepared, according to J. Med. Chem., 1999, 42,3510-3519, from 2-methyl-4-nitroaniline. A mixture of compound 14 and1-(1,1-dimethylethoxy)-N,N, N′,N′-tetramethyl-methanediamine in dry DMF(10 mL) was stirred at 70° C. for 2 h under N₂. After cooling to rt, thereaction mixture was treated with hexane, and the solid was collected byfiltration and washed with hexane to give compound 15 as black crystals.Compound 15 was converted to compound 17 in two alternate ways.

[0188] In one approach, compound 15 was converted to 17 by adding INLiHMDS to a solution of 15 in dry THF under N₂. The reaction mixture wasstirred at 65° C. for 2 h. After cooling to rt, 12 N HCl was added andthe reaction mixture stirred at 50° C. for 1 h. After cooling to rt, themixture was neutralized with sat'd NaHCO₃, the product extracted withEtOAc, and the organic layer washed with water and sat'd NaCl. Theproduct was concentrated and purified to give compound 17 as a yellowsolid.

[0189] Alternatively, compound 15 was converted to 17 by first mixingcompound 15 and 2,4-dimethoxylbenzylamine in DMF and stirring themixture at 140° C. for 3 h. The solvent was removed by vacuumdistillation and residue treated with EtOAc. The orange solid wascollected by filtration and washed with hexane to give compound 16. To asolution of compound 16 in anisole was added TFA. The reaction mixturewas stirred at 90° C. for 1 h and the solvent removed under reducedpressure. The residue was treated with sat'd NaHCO₃ (30 mL) and theproduct collected by filtration and washed with water to afford compound17. Compound 23 (366 mg, 1.93 mmol) and 2,4-dimethoxybenzaldehyde wereheated for 16 h at 125-130° C. with a stream of nitrogen passing in andout of the reaction flask, and sampling of the reaction mixture at 80°C. indicated conversion to compound 18.

[0190] To a solution of 18 and 2,4-dimethoxybenzaldehyde above in THFwas added sodium triacetoxyborohydride. The reaction was stirred for 22h and additional sodium triacetoxyborohydride (1.23 g, 5.8 mmol) wasadded. After 40 h, the reaction was concentrated to an oil which wastaken up in EtOAc, water, and dilute sodium bicarbonate. The EtOAc waswashed with water (3×), dried (sodium sulfate), and concentrated to anoily residue, which was purified to give compound 19a as a glassyresidue and 140 mg of compound 19b as an amorphous solid. Hydrogenationof compound 19a in EtOAc and MeOH in the presence 10% Pd/C for 1 h atone atmosphere afforded compound 20 as an amorphous solid.

[0191] Utility

[0192] The inventive compounds are inhibitors of the activatedcoagulation serine protease Factor VIIa and are selective versus FactorIXa, Factor Xa, Factor XIa, and/or thrombin as well as other serineproteases such as trypsin, chymotrypsin, and urokinase. Thus, thecompounds are useful for treating or preventing those processes whichinvolve the action of Factor VIIa. As used herein, the term “treating”or “treatment” is intended to encompass responsive measures designed tocure the disease or disorder, to delay the progression of the disease ordisorder, and/or to alleviate or lessen its symptoms, as well asprophylaxis measures designed to inhibit or delay the onset of thedisease or disorder and/or its symptoms.

[0193] In view of their above-referenced serine protease inhibitoryactivity, the inventive compounds are useful in treating consequences ofatherosclerotic plaque rupture including cardiovascular diseasesassociated with the activation of the coagulation cascade in thromboticor thrombophilic states. Such diseases include arterial thrombosis,coronary artery disease, acute coronary syndromes, myocardialinfarction, unstable angina, chronic stable angina, Prinzmetal's angina,ischemia resulting from vascular occlusion cerebral infarction, strokeand related cerebral vascular diseases (including cerebrovascularaccident and transient ischemic attack). Additionally, the compounds areuseful in treating or preventing formation of atherosclerotic plaques,transplant atherosclerosis, peripheral arterial disease and intermittentclaudication. In addition, the compounds can be used to preventrestenosis following arterial injury induced endogenously (by rupture ofan atherosclerotic plaque), or exogenously (by invasive cardiologicalprocedures such as vessel wall injury resulting from angioplasty).

[0194] The inventive compounds are also useful in preventing venousthrombosis, coagulation syndromes, deep vein thrombosis (DVT),disseminated intravascular coagulopathy, pulmonary embolism, cerebralthrombosis, atrial fibrillation, and cerebral embolism. The compoundsare useful in treating peripheral arterial occlusion, thromboemboliccomplications of surgery (such as hip replacement, endarterectomy,introduction of artificial heart valves, vascular grafts, and mechanicalorgans), implantation or transplantation of organ, tissue or cells, andthromboembolic complications of medications (such as oralcontraceptives, hormone replacement, and heparin, e.g., for treatingheparin-induced thrombocytopenia). The inventive compounds are useful inpreventing thrombosis associated with artificial heart valves, stents,and ventricular enlargement including dilated cardiac myopathy and heartfailure. The compounds are also useful in treating thrombosis due toconfinement (i.e. immobilization, hospitalization, bed rest etc.).

[0195] These compounds are also useful in preventing thrombosis andcomplications in patients genetically predisposed to arterial thrombosisor venous thrombosis (including activated protein C resistance,FV_(leiden), Prothrombin 20210, elevated coagulation factors FVII,FVIII, FIX, FX, FXI, prothrombin, TAFI and fibrinogen), elevated levelsof homocystine, and deficient levels of antithrombin, protein C, andprotein S. The inventive compounds may be used for treatingheparin-intolerant patients, including those with congenital andacquired antithrombin III deficiencies, heparin-inducedthrombocytopenia, and those with high levels of polymorphonucleargranulocyte elastase.

[0196] The present compounds may further be used to inhibit bloodcoagulation in connection with the preparation, storage, fractionation,or use of whole blood. For example, the compounds may be used tomaintain whole and fractionated blood in the fluid phase such asrequired for analytical and biological testing, e.g., for ex vivoplatelet and other cell function studies, bioanalytical procedures, andquantitation of blood-containing components. The compounds may be usedas anticoagulants in extracorpeal blood circuits, such as thosenecessary in dialysis and surgery (such as coronary artery bypasssurgery); for maintaining blood vessel patency in patients undergoingtransluminal coronary angioplasty, vascular surgery including bypassgrafting, arterial reconstruction, atherectomy, vascular graft and stentpatency, tumor cell metastasis, and organ, tissue, or cell implantationand transplantation.

[0197] In a particular embodiment, compounds of the present inventionare useful for treating any one or more of the aforementioned disordersirrespective of their etiology, e.g., for treating arterial thrombosis,coronary artery disease, acute coronary syndromes, myocardialinfarction, unstable angina, ischemia, transplant rejection, rheumatoidarthritis, inflammatory bowel disease, and/or viral infections.

[0198] The present invention also provides pharmaceutical compositionscomprising at least one compound of formula I, or a salt thereof,capable of treating a serine protease and/or a Factor-VIIa associateddisorder, in an amount effective therefor, alone or in combination withat least one additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant or vehicle. “Additional therapeutic agent”encompasses, but is not limited to, an agent or agents selected from thegroup consisting of immunosuppressants, potassium channel openers,calcium channel blockers, sodium hydrogen exchanger inhibitors,antiarrhythmic agents, antiatherosclerotic agents, anticoagulants suchas antithrombotic agents (Factor Xa inhibitors, anti-platelet agents, orplatelet aggregation inhibitors), prothrombolytic agents, fibrinogenantagonists, diuretics, anti-hypertensive agents, ATPase inhibitors,mineralocorticoid receptor antagonists, phospodiesterase inhibitors,antidiabetic agents, anti-inflammatory agents (steroidal andnon-steroidal), antioxidants, angiogenesis modulators, antiosteoporosisagents, hormone replacement therapies or hormone receptor modulators,oral contraceptives, antiobesity agents, antidepressants, antianxietyagents, antipsychotic agents, antiproliferative agents, antitumoragents, antiulcer and gastroesophageal reflux disease agents, growthhormone agents and/or growth hormone secretagogues, thyroid mimetics(including thyroid receptor antagonists), anti-infective agents,antiviral agents, antibacterial agents, antifungal agents,cholesterol/lipid lowering agents and lipid profile therapies, andagents that mimic ischemic preconditioning and/or myocardial stunning.

[0199] In the methods of the present invention, such other therapeuticagent(s) may be administered prior to, simultaneously with or followingthe administration of the compound(s) of the present invention.

[0200] Examples of suitable other anti-inflammatory agents with whichthe inventive compounds may be used include aspirin, non-steroidalantiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin), TNF-αinhibitors (such as tenidap and rapamycin or derivatives thereof), orTNF-α antagonists (e.g., infliximab, OR1384), prednisone, dexamethasone,Enbrel®, cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitorssuch as Naproxen®, Celebrex®, or Vioxx®), CTLA4-Ig agonists/antagonists,CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate(CellCept®), integrin antagonists, alpha-4 beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, ICAM-1,prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493,CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein kinaseinhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors,therapies for the treatment of irritable bowel syndrome (e.g., Zelmac®and Maxi-K® openers such as those disclosed in U.S. Pat. No. 6,184,231),or other NF-κB inhibitors, such as corticosteroids, calphostin, CSAIDs,4-substituted imidazo[1,2-A]quinoxalines as disclosed in U.S. Pat. No.4,200,750; Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; and nuclear translocation inhibitors, suchas deoxyspergualin (DSG).

[0201] Examples of suitable other antibiotics with which the inventivecompounds may be used include cyclosporins (e.g., cyclosporin A),CTLA4-Ig, antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac),anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86,monoclonal antibody OKT3, agents blocking the interaction between CD40and CD154 (a.k.a. “gp39”), such as antibodies specific for CD40 and/orCD154, fusion proteins constructed from CD40 and/or CD154/gp39 (e.g.,CD40Ig and CD8gp39), β-lactams (e.g., penicillins, cephalosporins andcarbopenams); β-lactam and lactamase inhibitors (e.g., augamentin);aminoglycosides (e.g., tobramycin and streptomycin); macrolides (e.g.,erythromycin and azithromycin); quinolones (e.g., cipro and tequin);peptides and deptopeptides (e.g. vancomycin, synercid and daptomycin)metabolite-based antibiotics (e.g., sulfonamides and trimethoprim);polyring systems (e.g., tetracyclins and rifampins); protein synthesisinhibitors (e.g., zyvox, chlorophenicol, clindamycin, etc.); andnitro-class antibiotics (e.g., nitrofurans and nitroimidazoles).

[0202] Examples of suitable other antifungal agents with which theinventive compounds may be used include fungal cell wall inhibitors(e.g., candidas), azoles (e.g., fluoconazole and vericonazole), andmembrane disruptors (e.g., amphotericin B). Examples of suitable otherantiviral agents for use with the inventive compounds includenucleoside-based inhibitors, protease-based inhibitors, viral-assemblyinhibitors, and other antiviral agents such as abacavir.

[0203] Other suitable therapeutic agents in combination with which theinventive compounds may be used include one or more of the following:

[0204] adenosine receptor modulators;

[0205] agents used to treat hypertension, heart failure, and/oratheroschlerosis, such as angiotensin-converting enzyme (ACE) inhibitors(e.g., captopril, lisinopril, zofenopril, ramipril, fosinopril,enalapril, ceranopril, cilazopril, delapril, pentopril, and quinapril),vasopeptidase inhibitors, i.e., dual ACE/NEP inhibitors (e.g.,omapatrilat and gemopatrilat), AT-1 receptor antagonists (e.g.,losartan, irbesartan, and valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan, and compounds disclosed in U.S. Pat. No.5,612,359 and U.S. Pat. No. 6,043,265), Dual ET/AII antagonists (e.g.,compounds disclosed in WO 00/01389), neutral endopeptidase (NEP)inhibitors, and Rho-kinase inhibitors;

[0206] agents for inhibiting F₁F₀-ATPase, including efrapeptin,oligomycin, autovertin B, azide, and compounds described in WO 03/05026;

[0207] alpha- or beta-adrenergic blockers (such as propranolol, nadolol,carvedilol, and prazosin), or -β-adrenergic agonists (such as albuterol,terbutaline, formoterol, salmeterol, bitolterol, pilbuterol, andfenoterol);

[0208] angiogenesis modulators such as endostatin;

[0209] anotropic agents such as calcium channel blocking agents (tand 1) including verapamil, nifedipine, diltiazem, amlodipine, andmibefradil;

[0210] antianginal agents such as nitrates, for example, sodiumnitrates, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate,and nitrovisodilators;

[0211] antiarrhythmic agents including Class I agents (such aspropafenone); Class II agents (propranolol); Class III agents (such assotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IVagents (such as ditiazem and verapamil); K⁺ channel openers such asI_(Ach) inhibitors and inhibitors of the K_(ν)1 subfamily of K⁺ channelopeners such as I_(Kur) inhibitors (e.g., compounds disclosed in U.S.Publication US 20030022890); and gap-junction modulators such asconnexions;

[0212] anticholinergics such as ipratropium bromide;

[0213] anticoagulant or antithrombotic agents including aspirin,warfarin, ximelagtran, low molecular weight heparins (such as lovenox,enoxaparain, and dalteparin), anti-platelet agents such as GPIIb/GPIIIablockers, (e.g., abciximab, eptifibatide, and tirofiban), thromboxanereceptor antagonists (e.g., ifetroban), P2Y₁ and P2Y₁₂ antagonists(e.g., clopidogrel, ticlopidine, CS-747, and aspirin/clopidogrelcombinations), and Factor Xa inhibitors (e.g., fondaparinux andrazaxaban);

[0214] antidiabetic agents such as biguanides (e.g. metformin),glucosidase inhibitors (e.g. acarbose), insulins (including insulinsecretagogues or insulin sensitizers), meglitinides (e.g. repaglinide),sulfonylureas (e.g., glimepiride, glyburide and glipizide),biguanide/glyburide combinations (e.g., glucovance), thiozolidinediones(e.g. troglitazone, rosiglitazone and pioglitazone), PPAR-alphaagonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2inhibitors, inhibitors of fatty acid binding protein (aP2) such as thosedisclosed in U.S. Pat. No. 6,548,529 assigned to the present assignee,glucagon-like peptide-1 (GLP-1), glucagon phosphorylase, and dipeptidylpeptidase IV (DP4) inhibitors;

[0215] antidepressant, antianxiety or antipsychotic agents such asnefazodone, sertraline, diazepam, lorazepam, buspirone, and hydroxyzinepamoate;

[0216] antioxidants and/or lipid peroxidation inhibitors such asprobucol, BO-653, Vitamin A, Vitamin E, and AGI-1067;

[0217] antiosteoporosis agents such as alendronate and raloxifene;

[0218] antiobesity agents such as orlistat and aP2 inhibitors (such asthose disclosed in U.S. Pat. No. 6,548,529;

[0219] antiproliferative agents such as cyclosporin A, paclitaxel, FK506, and adriamycin;

[0220] antiulcer and gastroesophageal reflux disease agents such asfamotidine, ranitidine, and omeprazole;

[0221] cardiac glycosides such as sodium calcium exchange inhibitors anddigitalis;

[0222] diuretics such as sodium-hydrogen exchange inhibitors,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, and amiloride;

[0223] hormone replacement therapies such as estrogen (e.g., congugatedestrogens) and estradiol, and hormone receptor modulators such asandrogen receptor modulators;

[0224] lipid profile modulators including HMG-CoA reductase inhibitors(e.g., pravastatin, simvastatin, atorvastatin, fluvastatin,cerivastatin, AZ4522, itavastatin [Nissan/Kowa]), ZD-4522 (a.k.a.rosuvastatin, atavastatin or visastatin), squalene synthetaseinhibitors, fibrates, bile acid sequestrants (such as questran), niacinand niacin/statin combinations, ACAT1 inhibitors, ACAT2 inhibitors, dualACAT1/2 inhibitors, microsomal triglyceride transport protein inhibitors(such as disclosed in U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279and U.S. Pat. No. 5,760,246), cholesterol absorption inhibitors,cholesterol ester transfer protein inhibitors (e.g., CP-529414),PPAR-delta agonists, PPAR-alpha agonists, dual PPAR-alpha/deltaagonists, LXR-alpha agonists, LXR-beta agonists, LXR dual alpha/betaagonists, and SCAP modulators;

[0225] mineralocorticoid receptor antagonists such as spironolactone andeplerenone;

[0226] phosphodiesterase (PDE) inhibitors that block the hydrolysis cAMPand/or cGMP including dipyridamole, cilostazol, sildenafil, rolipram,denbutyline, theophylline (1,2-dimethylxanthine), and ARIFLO™ (i.e.,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid), or PDE inhibitors in combination with anti-platelet agents;

[0227] prostacyclin mimetics such as berapist;

[0228] serotonin-2-receptor antagonists (such as ketanserin);

[0229] sodium hydrogen exchange-1 (NHE-1) inhibitors such as cariporideand zoniporide;

[0230] thrombolytic agents such as tissue plasminogen activator (naturalor recombinant), streptokinase, reteplase, activase, lanoteplase,urokinase, prourokinase, tenecteplase (TNK), lanoteplase (nPA),anisolated streptokinase plasminogen activator complex (ASPAC), animalsalivary gland plasminogen activators, PAI-1 inhibitors such as XR-330and T-686, procarboxy peptidase-U, TAFI inhibitors, and inhibitors ofα-2-antiplasmin such as anti-α-2-antiplasmin antibody;

[0231] urotensin modulators; and

[0232] vasopressin receptor antagonists.

[0233] The above other therapeutic agents, when employed in combinationwith the compounds of the present invention, may be used in the samedosage form with the compound of formula I, in different dosage forms,in those amounts indicated in the Physicians' Desk Reference (PDR),and/or as otherwise determined by one of ordinary skill in the art.

[0234] The compounds of the present invention may act in a synergisticfashion with one or more of the above agents to allow for increasedefficacy and/or reduced doses of any of the above agents and thereforeminimize potential side-effects such as potential hemorrhagic sideeffects.

[0235] The term “pharmaceutically acceptable carrier, adjuvant orvehicle” refers to a carrier, adjuvant or vehicle that may beadministered to a subject, together with a compound of the presentinvention, and which does not destroy the pharmacological activitythereof. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of the presentinvention include, but are not limited to, the following: ionexchangers, alumina, aluminum stearate, lecithin, self-emulsifying drugdelivery systems (“SEDDS”) such as d(tocopherol polyethyleneglycol 1000succinate), surfactants used in pharmaceutical dosage forms such asTweens or other similar polymeric delivery matrices, serum proteins suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β- and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be used to enhance delivery of the compounds of the presentinvention.

[0236] The compositions of the present invention may contain othertherapeutic agents as described below, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

[0237] The compounds of the formula I may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; buccally; parenterally,such as by subcutaneous, intravenous, intramuscular, or intrasternalinjection or infusion techniques (e.g., as sterile injectable aqueous ornon-aqueous solutions or suspensions); nasally such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds may, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release may be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds mayalso be administered liposomally.

[0238] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The present compounds mayalso be delivered through the oral cavity by sublingual and/or buccaladministration. Molded tablets, compressed tablets or freeze-driedtablets are exemplary forms which may be used. Exemplary compositionsinclude those formulating the present compound(s) with fast dissolvingdiluents such as mannitol, lactose, sucrose and/or cyclodextrins. Alsoincluded in such formulations may be high molecular weight excipientssuch as celluloses (avicel) or polyethylene glycols (PEG). Suchformulations may also include an excipient to aid mucosal adhesion suchas hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose(HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydridecopolymer (e.g., Gantrez), and agents to control release such aspolyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use.

[0239] Exemplary compositions for nasal aerosol or inhalationadministration include solutions in saline which may contain, forexample, benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

[0240] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal,intralesional and intracranial injection or infusion techniques.

[0241] Exemplary compositions for rectal administration includesuppositories which may contain, for example, a suitable non-irritatingexcipient, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures, butliquify and/or dissolve in the rectal cavity to release the drug.

[0242] Exemplary compositions for topical administration include atopical carrier such as Plastibase (mineral oil gelled withpolyethylene).

[0243] The effective amount of a compound of the present invention maybe determined by one of ordinary skill in the art, and includesexemplary dosage amounts for an adult human of from about 0.1 to 500mg/kg of body weight of active compound per day, which may beadministered in a single dose or in the form of individual divideddoses, such as from 1 to 5 times per day. It will be understood that thespecific dose level and frequency of dosage for any particular subjectmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the species, age, body weight,general health, sex and diet of the subject, the mode and time ofadministration, rate of excretion, drug combination, and severity of theparticular condition. Preferred subjects for treatment include animals,most preferably mammalian species such as humans, and domestic animalssuch as dogs, cats and the like, subject to Factor-VIIa associateddisorders.

[0244] Factor VIIA Assay

[0245] The effectiveness of compounds of the present invention asinhibitors of the coagulation factor VIIa, as well as selectivity versusfactors Ixa, Xa, XIa, or thrombin, can be determined using a relevantpurified serine protease, respectively, and an appropriate syntheticsubstrate. The rate of hydrolysis of the chromogenic substrate by therelevant serine protease was measured both in the absence and presenceof compounds of the present invention. Hydrolysis of the substrateresulted in the release of pNA (para-nitroaniline), which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nM, or the release of AMC (amino methylcoumarin, which was monitoredspectrofluorometrically by measuring the increase in emission at 460 nMwith excitation at 380 nM. A decrease in the rate of absorbance changeat 405 nM in the presence of inhibitor is indicative of enzymeinhibition. Such methods are known to one skilled in the art. Theresults of this assay are expressed as inhibitory constant, K_(i).

[0246] Factor VIIa determinations were made in 0.005 M calcium chloride,0.15 M sodium chloride, 0.05 M HEPES buffer containing 0.5% PEG 8000 ata pH of 7.4. Determinations were made using purified human Factor Vlla(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 2-5 nM, recombinant solubletissue factor at a concentration of 18-35 nM and the synthetic substrateH-D-Ile-Pro-Arg-pNA (S-2288; Chromogenix or BMPM-2; AnaSpec) at aconcentration of 0.001 M. Compounds tested in the assay for Factor VIIaare considered to be active if they exhibit a K_(i) of equal to or lessthan 25 μM. Preferred compounds of the present invention have K_(i)'s ofequal to or less than 1 μM. More preferred compounds of the presentinvention have K_(i)'s of equal to or less than 0.1 μM. Even morepreferred compounds of the present invention have K_(i)'s of equal to orless than 0.01 μM. Compounds of the present invention have demonstratedK_(i) values of equal to or less than 25 μM in the assay for FactorVIIa, thereby confirming the utility of the compounds of the presentinvention as effective inhibitors of coagulation factor VIIa and asanticoagulants for treatment of thromboembolic disorders.

[0247] Factor IXa determinations were made in 0.005 M calcium chloride,0.1 M sodium chloride, 0.05 M TRIS base and 0.5% PEG 8000 at a pH of7.4. Determinations were made using purified human Factor IXa(Haematologic Technologies) at a final assay concentration of 20-100 nMand the synthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa3688 (H-D-Leu-Phe-Gly-Arg-AMC; CenterChem) at a concentration of0.0004-0.0005 M. Compounds tested in the Factor IXa assay are consideredto be active if they exhibit a K_(i) of equal to or less than 25 μM.

[0248] Factor Xa determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human Factor Xa(Haematologic Technologies) at a final assay concentration of 150-1000pM and the synthetic substrate S-2222 (Bz-Ile-Glu(gamma-OMe,50%)-Gly-Arg-pNA; Chromogenix) at a concentration of 0.0002-0.0003 M.Compounds tested in the Factor Xa assay are considered to be active ifthey exhibit a K_(i) of equal to or less than 25 μM.

[0249] Factor XIa determinations were made in 50 mM HEPES buffer at pH7.4 containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 75-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002-0.00025M. Compounds tested in the Factor XIa assay are considered to be activeif they exhibit a K_(i) of equal to or less than 25 μM.

[0250] Thrombin determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002 M.Compounds tested in the thrombin assay are considered to be active ifthey exhibit a K_(i) of equal to or less than 25 μM.

[0251] The Michaelis constant, K_(m), for substrate hydrolysis by eachprotease was determined at 25° C. using the method of Lineweaver andBurk. Values of K_(i) were determined by allowing the protease to reactwith the substrate in the presence of the inhibitor. Reactions wereallowed to go for periods of 20-180 minutes (depending on the protease)and the velocities (rate of absorbance change vs time) were measured.The following relationship was used to calculate K_(i) values:

[0252] (v_(O)−v_(S))/v_(S)=I/(K_(i)(1+S/K_(m))) for a competitiveinhibitor with one binding site; or

[0253] v_(S)/v_(O)=A+((B−A)/1+((IC₅₀/(I)^(n)))) and

[0254] K_(i)=IC₅₀/(1+S/K_(m)) for a competitive inhibitor

[0255] where:

[0256] v_(O) is the velocity of the control in the absence of inhibitor;

[0257] v_(S) is the velocity in the presence of inhibitor;

[0258] I is the concentration of inhibitor;

[0259] A is the minimum activity remaining (usually locked at zero);

[0260] B is the maximum activity remaining (usually locked at 1.0);

[0261] n is the Hill coefficient, a measure of the number andcooperativity of potential inhibitor binding sites;

[0262] IC₅₀ is the concentration of inhibitor that produces 50%inhibition under the assay conditions;

[0263] K_(i) is the dissociation constant of the enzyme: inhibitorcomplex;

[0264] S is the concentration of substrate; and

[0265] K_(m) is the Michaelis constant for the substrate.

[0266] The effectiveness of compounds of the present invention asinhibitors of the coagulation factor VIIa can be determined usingrelevant in vivo thrombosis models, including In VivoElectrically-induced Carotid Artery Thrombosis Models and In Vivo RabbitArterio-venous Shunt Thrombosis Models.

[0267] In Vivo Electrically-induced Carotid Artery Thrombosis Model:

[0268] The antithrombotic effect of compounds of the present inventioncan be demonstrated in the electrically-induced carotid arterythrombosis (ECAT) model in rabbits. In this model, rabbits areanesthetized with a mixture of ketamine (50 mg/kg i.m.) and xylazine (10mg/kg i.m.). A femoral vein and a femoral artery are isolated andcatheterized. The carotid artery is also isolated such that its bloodflow can be measured with a calibrated flow probe that is linked to aflowmeter. A stainless steel bipolar hook electrode is placed on thecarotid artery and positioned caudally in relationship to the flow probeas a means of applying electrical stimulus. In order to protect thesurrounding tissue, a piece of Parafilm is placed under the electrode.

[0269] Test compounds are considered to be effective as anticoagulantsbased on their ability to maintain blood flow in the carotid arteryfollowing the induction of thrombosis by an electrical stimulus. A testcompound or vehicle is given as continuous intravenous infusion via thefemoral vein, starting 1 h before electrical stimulation and continuingto the end of the test. Thrombosis is induced by applying a directelectrical current of 4 mA for 3 min to the external arterial surface,using a constant current unit and a d.c. stimulator. The carotid bloodflow is monitored and the time to occlusion (decrease of blood flow tozero following induction of thrombosis) in minutes is noted. The changein observed blood flow is calculated as a percentage of the blood flowprior to induction of thrombosis and provides a measure of the effect ofa test compound when compared to the case where no compound isadministered. This information is used to estimate the ED₅₀value, thedose that increases blood flow to 50% of the control (blood flow priorto induction of thrombosis) and is accomplished by nonlinear leastsquare regression.

[0270] In Vivo Rabbit Arterio-venous Shunt Thrombosis Model:

[0271] The antithrombotic effect of compounds of the present inventioncan be demonstrated in a rabbit arterio-venous (AV) shunt thrombosismodel. In this model, rabbits weighing 2-3 kg anesthetized with amixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) areused. A saline-filled AV shunt device is connected between the femoralarterial and the femoral venous cannulae. The AV shunt device consistsof a piece of 6-cm tygon tubing that contains a piece of silk thread.Blood will flow from the femoral artery via the AV-shunt into thefemoral vein. The exposure of flowing blood to a silk thread will inducethe formation of a significant thrombus. After forty minutes, the shuntis disconnected and the silk thread covered with thrombus is weighed.Test agents or vehicle will be given (i.v., i.p., s.c., or orally) priorto the opening of the AV shunt. The percentage inhibition of thrombusformation is determined for each treatment group. The ID₅₀ values (dosewhich produces 50% inhibition of thrombus formation) are estimated bylinear regression.

[0272] The following examples illustrate preferred embodiments of thepresent invention and do not limit the scope of the present inventionwhich is defined in the claims. Abbreviations are employed in theExamples and Schemes set forth below for ease of reference as follows:

[0273] Abbreviations

[0274] Me=methyl

[0275] Et=ethyl

[0276] MeOH=methanol

[0277] EtOH=ethanol

[0278] i-PrOH=isopropanol

[0279] Ph=phenyl

[0280] Bn=benzyl

[0281] t-Bu=tertiary butyl

[0282] Boc=tert-butoxycarbonyl

[0283] AcOH=acetic acid

[0284] i-Pr₂NEt=diisopropylethylamine

[0285] CBZ=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

[0286] EtOAc=ethyl acetate

[0287] CDI=carbonyl dimidazole

[0288] DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene

[0289] DMF=dimethyl formamide

[0290] DMSO=dimethyl sulfoxide

[0291] DME=1,2 dimethoxyethane

[0292] DCE=1,2 dichloroethane

[0293] DCM=dichloromethane

[0294] DMAP=4-dimethylaminopyridine

[0295] DCC=dicyclohexylcarbodiimide

[0296] DIC or DIPCDI=diisopropylcarbodiimide

[0297] DIAD=diisopropyl azodicarboxylate

[0298] DIPEA=diisopropylethylamine

[0299] DPPF=1,1′-bis(diphenylphosphino)ferrocene

[0300] DEPBT=3-(diethoxyphosphoryloxy)-1, 2, 3-benzotriazin-4(3H)-one

[0301] DMB=2,4-dimethoxy-benzyl

[0302] NMM=N-methyl morpholine

[0303] NaHCO₃=sodium bicarbonate

[0304] NaBH(OAc)₃=sodium triacetoxyborohydride

[0305] EDC (or EDC.HCl) or EDCI (or EDCI.HCl) orEDAC=3-ethyl-3′(dimethylamino)propyl-carbodiimide hydrochloride (or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)

[0306] HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate

[0307] HOAT=1-Hydroxy-7-azabenzotriazole

[0308] HATU=[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

[0309] HBTU=O-benzotriazol-1-yl-n,n,n′,n′-tetramethyluroniumhexafluorophosphate

[0310] Py-Brop=bromo-tris-pyrolidino phosphonium hexafluorophosphate

[0311] Pd/C=palladium on carbon

[0312] Pd(OAc)₂=Palladium acetate

[0313] SAX=Strong Anion Exchanger

[0314] SCX=Strong Cation Exchanger

[0315] PVP=polyvinylpyridine

[0316] THF=tetrahydrofuran

[0317] TFA=trifluoroacetic acid

[0318] TEA=triethylamine

[0319] TBS=t-butyldimethylsilyl

[0320] Tf=trifluoromethanesulfonyl

[0321] L=liter

[0322] mL=milliliter

[0323] μL=microliter

[0324] g=gram(s)

[0325] mg=milligram(s)

[0326] meq=milliequivalent

[0327] rt or RT=room temperature

[0328] conc.=concentrated

[0329] sat or sat'd=saturated

[0330] TLC=thin layer chromatography

[0331] HPLC=high performance liquid chromatography

[0332] RP HPLC=reverse phase HPLC

[0333] LC/MS=high performance liquid chromatography/mass spectrometry

[0334] MS or Mass Spec=mass spectrometry

[0335] MW=molecular weight

[0336] mp=melting point

EXAMPLE 1

[0337]2-(4-Aminomethyl-phenylamino)-N-benzyl-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide

[0338]N-Benzyl-2-(4-cyano-phenylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide(150 mg, 0.34 mM) (prepared according to U.S. Pat. No. 6,472,393), wasdissolved in 15 mL MeOH. Raney-Ni (30 mg) and AcOH (0.11 nL) were added.After Parr hydrogenation at 35 psi H₂ pressure for 48 h, the acetamidewas consumed. After filtration and concentration the residue wasdissolved in 2 mL dioxane/water (1:1), and HCl (100 μL, 1.0N aq.solution) was added. Lyophilation yielded the dihydrochloride salt ofExample 2 (36 mg) as a white solid with a HPLC-purity of 82%. Thismaterial was further purified by prep-HPLC yielding 14 mg pure Example 1(8.5%). LR-MS, M-H 446.2.

EXAMPLE 2

[0339]7-{[Carboxy-(3-ethoxy-4-isopropoxy-phenyl)-methyl]-amino}-3,4-dihydro-1H-isoquinoline-2-carboxylicacidtert-butyl ester

[0340] 2A

[0341]7-{[(3-Ethoxy-4-isopropoxy-phenyl)-methoxycarbonyl-methyl]-amino}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

[0342] 7-Amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (99.33 mg, 0.40 mmol) and 3-ethoxy-4-isopropoxy-benzaldehyde(83.30 mg, 0.40 mmol) were dissolved into anhydrous MeOH (2.0 mL) andheated at 60° C. for 3.5 h. The mixture was cooled to rt and benzylisonitrile (48.71 μL, 0.40 mmol) was added. The reaction was cooled to0° C. and boron trifluoride diethyl etherate (152.07 μL, 1.20 mmol) wasadded in two aliquots. The reaction was allowed to warm to rt withshaking overnight. Water (60 μL) was added and the reaction was shakenat rt for one hour and concentrated. The residual oil was redissolvedinto EtOAc and washed with water (3×) and brine, dried over anhydrousNa₂SO₄, filtered, and concentrated. (The Boc protecting group fell offduring the synthesis to give the free secondary amine.) The free amineproduct was captured on cation exchange resin and eluted off withammonia in MeOH. The product was purified by preparative HPLC. Thepurified product (22.7 mg, 0.0570 mmol) was dissolved into anhydrous DCM(1.0 mL). TEA (9.54 μL, 0.0684 mmol) and DMAP (0.70 mg, 0.0057 mmol)were added. The reaction was cooled to 0° C. and di-tert-butyldicarbonate (14.94 mg, 0.0684 mmol) was added. The reaction was allowedto warm to rt with shaking overnight and concentrated. The residue wasdissolved into EtOAc and washed with sat'd NaHCO₃, water and brine,dried over anhydrous Na₂SO₄, filtered, and concentrated to yield 2Awhich was used in the subsequent step without further purification.

[0343] 2B (Example 2)

[0344] Compound 2A was dissolved into THF (1.5 mL). 2N LiOH (0.50 mL)was added. The reaction was vortexed at rt for 6.5 h. It was thenconcentrated to remove the THF. The residual oil was redissolved intowater. Ice was added. This solution was acidified with 1N HCl andextracted with EtOAc. The combined EtOAc extracts were washed with waterand brine, dried over anhydrous sodium sulfate, filtered andconcentrated to yield 2B, Example 2.

EXAMPLE 3

[0345][3-(tert-Butoxycarbonylamino-methyl)-phenylamino]-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid

[0346] 3A

[0347][3-(tert-Butoxycarbonylamino-methyl)-phenylamino]-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid methyl ester

[0348] Compound 3A was prepared following the same or similar procedureas described above for 2A, except (3-amino-benzyl)-carbamic acidtert-butyl ester (88.91 mg, 0.40 mmol) was used instead of7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester.

[0349] 3B (Example 3)

[0350] Compound 3B was prepared from 3A following the same or simliarprocedure described above in 2B.

EXAMPLE 4

[0351](1-Amino-isoquinolin-6-ylamino)-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid

[0352] 4A

[0353] (3-Ethoxy-4-isopropoxy-phenyl)-hydroxy-acetic acid methyl ester

[0354] To a solution of 3-ethoxy-4-isopropoxy-benzaldehyde (4.17 g, 20mM) in DCM at −5° C. was added trimethylsilylcyanide (9.92 g, 0.1 M)followed by boron trifluoride etherate (1.0 mL). The solution wasstirred for 4 days at rt. The reaction was monitored by consumption of3-ethoxy-4-isopropoxy-benzaldehyde. The solution was concentrated invacuo and the resulting oily residue was dissolved in dry ether (50 mL).MeOH (3.8 mL, 60 mM) was added followed by a solution of HCL in ether(60 mL of a 1.0M solution). The reaction solution was kept at −10° C.for 2 h and at 5° C. for 24 h. 4.44 g of white crystals formed whichwere filtered and washed with ether. The crystals were dissolved inwater (25 mL) and DCM (25 mL) and stirred for 1 h at rt. The two phaseswere separated and the aqueous layer was extracted with DCM. Thecombined organic extracts were washed with brine, dried over sodiumsulfate and concentrated to afford 3.52 g of compound 4A as a oil whichcrystallized to an off-white solid over several days.

[0355] 4B

[0356] Bromo-(3-ethoxy-4-isopropoxy-phenyl)-acetic acid methyl ester

[0357] (3-Ethoxy-4-isopropoxy-phenyl)-hydroxy-acetic acid methyl ester5A (100 mg, 0.37 mmol) was dissolved into anhydrous DCM (8.0 mL) andintroduced into an oven-dried round bottom flask under argon. Resinbound triphenylphosphine (740 mg, 2.236 mmol), bromine (48 μL, 0.9269mmol) and imidazole (26 mg, 0.3809 mmol) were added sequentially. Thereaction was stirred at rt for 3 h. The resin was filtered off andwashed with DCM. The filtrate was concentrated down. The resulting solidwas triturated with diethyl ether. The insoluble solid was filtered awayfrom the ethereal solution which was in turn concentrated down to yield83 mg of 4B as a colorless oil of 52% purity by HPLC analysis. Thismaterial was used for the next step without further purification.

[0358] 4C

[0359]{1-[Bis-(2,4-dimethoxy-benzyl)-amino]-isoquinolin-6-ylamino}-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid methyl ester

[0360] A solution ofN′,N′-Bis-(2,4-dimethoxy-benzyl)-isoquinoline-1,6-diamine (38 mg, 0.0827mmol) (compound 20, Scheme G), in anhydrous DCM (5 mL) was added to neat4B (83 mg, 0.2506 mmol). DIEA (44 μL, 0.2506 mmol) was added and thereaction was stirred overnight at rt. The reaction mixture wasconcentrated to yield 123 mg of 4C a yellow oil which was purified bycolumn chromatography on silica gel using 20-40% EtOAc in hexane.

[0361] 4D

[0362]{1-[Bis-(2,4-dimethoxy-benzyl)-amino]-isoquinolin-6-ylamino}-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid

[0363] Compound 4C (22.2 mg) was dissolved in THF (1.5 mL). 2N LiOH (0.5ml) was added, and the reaction mixture was stirred at RT for 4 h. TheTHF was evaporated. The residual oil was diluted with water andextracted with EtOAc. The basic aqueous solution was acidified to pH 1.0with conc. HCl and extracted with EtOAc. The combined organic extractswere washed with water and brine, dried over anhydrous sodium sulfate,filtered and concentrated to afford 4D (18.9 mg, 87%) as a glassy yellowsolid of 70% purity by LC/MS. This material was used in the next stepwithout further purification.

[0364] 4E (Example 4)

[0365] Compound 4D (6.0 mg) was dissolved into anisole (0.20 ml) andcooled to 0° C. TFA (0.20 mL) was added. The reaction was stirred at 0°C. for 15 min and then quenched to pH 9 with TEA at 0° C. The reactionmixture was concentrated and the resulting oil was filtered through aC18 cartridge and then purified by preparative HPLC to afford the TFAsalt of 4E (0.6 mg) as an orange oil ((M+H)+=396, HPLC RetentionTime=2.42 min, column: Phenominex 4.6 mm×50 mm, 0-100% B 4 min gradient,Solvent A=10% MeOH−90% H₂O−10 mM NH₄Ac, Solvent B=90% MeOH−10% H₂O−10 mMNH₄Ac, 4 ml/min, Wavelength=220).

EXAMPLE 5

[0366]2-(1-Amino-isoquinolin-6-ylamino)-N-benzyl-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide

[0367] 5A

[0368]N-Benzyl-2-{1-[bis-(2,4-dimethoxy-benzyl)-amino]-isoquinolin-6-ylamino}-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide

[0369] The carboxylic acid 4D (4.2 mg, 0.0060 mmol) was dissolved intoanhydrous THF (0.50 mL). DEPBT (3.6 mg, 0.0120 mmol) and TEA (1.68 μL,0.0120 mmol) were added. Benzylamine (0.98 μL, 0.0090 mmol) was addedand the reaction mixture was stirred overnight at rt. The reactionmixture was concentrated down and used crude in the next step.

[0370] 5B (Example 5)

[0371] Compound 5A was treated with 1/1 TFA/anisole at 0° C. for 30mins. The reaction was quenched with TEA and the mixture was filteredthrough a C18 cartridge. The filtrate was concentrated and the residuepurified by preparative HPLC to afford the TFA salt of 5B (0.50 mg) as acolourless oil. ((M+H)+=485, HPLC Retention Time=3.06 min, column:Phenominex 4.6 mm X 50 mm, 0-100% B 4 min gradient, Solvent A=10%MeOH−90% H₂O−10 mM NH₄Ac, Solvent B=90% MeOH−10% H₂O−10 mM NH₄Ac, 4ml/min, Wavelength=220).

We claim:
 1. A compound according to formula (I),

or a stereoisomer or a pharmaceutically-acceptable salt thereof,wherein: X is —OH, —O(alkyl), —O(aryl), —O(arylalkyl), —NR₅(aryl), or—NR₅(arylalkyl); wherein said aryl or arylalkyl are optionallysubstituted with one to two R₂₅; W is hydrogen or —(CR₇R₈)_(q)—H; Z is a5-membered heteroaryl group optionally substituted with 1-3 R₉, a fiveto six membered heterocyclo or cycloalkyl group optionally substitutedwith 1-3 R₉, a 9 to 10 membered bicyclic aryl or heteroaryl optionallysubstituted with 1-3 substituents selected from R₉ and/or R₁₀, or

Z, Z₂ and Z₃ are independently N or CR₉; R₁, R₂ and R₃ are attached toany available carbon atom of phenyl ring A and are independentlyselected from hydrogen, halogen, cyano, nitro, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,substituted C₁₋₁₀alkyl, substituted C₂₋₁₀alkenyl, —C(═O)NR₁₂R₁₃, —OR₁₂,—CO₂R₁₂, —C(═O)R₁₂, —SR₁₂, —S(O)_(t)R₁₅, —NR₁₂R₁₃, —NR₁₂SO₂R₁₅,—NR₁₄SO₂NR₁₂R₁₃, —NR₁₂CO₂R₁₃, —NR₁₂C(═O)R₁₃, —NR₁₄C(═O)NR₁₂R₁₃,—SO₂NR₁₂R₁₃, aryl, heteroaryl, cycloalkyl, and heterocyclo; R₅ ishydrogen, C₁₋₄alkyl, NH₂, C₁₋₄alkylamino, hydroxy, or C₁₋₄alkoxy; R₇ andR₈ are independently selected from hydrogen, —OR₁₈, —NR₁₈R₁₉,—NR₁₈SO₂R₂₀, alkyl, alkenyl, substituted alkyl, substituted alkenyl,halogen, haloalkyl, haloalkoxy, cyano, nitro, alkylthio, —C(═O)H, acyl,—CO₂H, alkoxycarbonyl, sulfonamido, sulfonyl, and phenyl in turnoptionally substituted with 1-3 of halogen, cyano, haloalkyl,haloalkoxy, nitro, hydroxy, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,amino, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, and/or C₁₋₄aminoalkyl; R₉, R₁₀ andR₁₁ are independently selected from hydrogen, halogen, alkyl,substituted alkyl, haloalkyl, haloalkoxy, cyano, nitro, —S(O)_(u)R₂₁,—NR₂₂SO₂R₂₁, —C(═O)NR₂₂R₂₃, —OR₂₂, —CO₂R₂₂, —C(═O)R₂₂, —SR₂₂, —NR₂₂R₂₃,—NR₂₂CO₂R₂₃, —NR₂₂C(═O)R₂₃, —NR₂₂C(═O)NR₂₃R₂₄, —SO₂NR₂₂R₂₃,—NR₂₂SO₂NR₂₃R₂₄, —C(═NR₂₂)NR₂₃R₂₄, five or six membered heterocyclo orheteroaryl, phenyl, and C₃₋₇cycloalkyl, provided that R₁₁ is not—C(═NR₂₂)NR₂₃R₂₄ when W or W₁ is hydrogen; wherein when R₉, R₁₀ or R₁₁is selected from heterocyclo, heteroaryl, phenyl, and C₃₋₇cycloalkyl,each of said cyclic groups in turn is optionally substituted with up tothree of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄ hydroxyalkyl, C₁₋₄ aminoalkyl,halogen, hydroxy, haloalkyl, haloalkoxy, amino, C₁₋₄ alkylamino, and/orcyano; R₁₂, R₁₃, R₁₄, R₁₈, R₁₉, R₂₂ R₂₃, and R₂₄ are independentlyselected from hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; R₁₅, R₂₀ and R₂₁are independently selected from alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; R₂₅at each occurrence is selected from hydrogen, halogen, cyano, nitro,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, substituted C₁₋₁₀alkyl, substitutedC₂₋₁₀alkenyl, —C(═O)NR₁₂R₁₃, —OR₁₂, —CO₂R₁₂, —C(═O)R₁₂, —SR₁₂,—S(O)_(t)R₁₅, —NR₁₂R₁₃, —NR₁₂SO₂R₁₅, —NR₁₄SO₂NR₁₂R₁₃, —NR₁₂CO₂R₁₃,—NR₁₂C(═O)R₁₃, —NR₁₄C(═O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, aryl, heteroaryl,cycloalkyl, and heterocyclo; p is 1 or 2; q is 1, 2 or 3; t is 1 or 2;and u is 1 or 2; provided that when Z is phenyl, pyridyl or pyridazinyl,R₉, R₁₀ and/or R₁₁ are other than cyano or —C(═NR₂₂)NR₂₃R₂₄.
 2. Acompound according to claim 1, or a stereoisomer or apharmaceutically-acceptable salt thereof, wherein the compound is offormula (Ia):

X is —OH, —O(phenyl) optionally substituted with one to two R₂₅,—O(benzyl) optionally substituted with one to two R₂₅, —NH(phenyl)optionally substituted with one to two R₂₅, or —NH(benzyl) optionallysubstituted with one to two R₂₅; W is hydrogen or —(CH₂)_(q)—H; Z isselected from a 5-membered heteroaryl group optionally substituted with1-3 R₉, a five to six membered heterocyclo or cycloalkyl groupoptionally substituted with 1-3 R₉, a 9 to 10 membered bicyclic aryl orheteroaryl optionally substituted with 1-3 substituents selected from R₉and/or R₁₀, and

Z₁, Z₂ and Z₃ are independently N or CR₉ and at least one of Z₁, Z₂ andZ₃ is N; R₁ and R₂ are independently selected from hydrogen, halogen,cyano, nitro, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, substituted C₁₋₁₀alkyl,substituted C₂₋₁₀alkenyl, —C(═O)NR₁₂R₁₃, —OR₁₂, —CO₂R₁₂, —C(═O)R₁₂,—SR₁₂, —S(O), R₁₅, —NR₁₂R₁₃, —NR₁₂SO₂R₁₅, —NR₁₄SO₂NR₁₂R₁₃, —NR₁₂C₂R₁₃,—NR₁₂C(═O)R₁₃—NR₁₄C(═O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, aryl, heteroaryl,cycloalkyl, and heterocyclo; R₉, R₁₀ and R₁₁ are independently selectedfrom hydrogen, halogen, alkyl, substituted alkyl, haloalkyl, haloalkoxy,cyano, nitro, —S(O)_(u)R₂₁, —NR₂₂SO₂R₂₁, —C(═O)NR₂₂R₂₃, —OR₂₂, —CO₂R₂₂,—C(═O)R₂₂, —SR₂₂, —NR₂₂R₂₃, —NR₂₂CO₂R₂₃, —NR₂₂C(═O)R₂₃,—NR₂₂C(═O)NR₂₃R₂₄, —SO₂NR₂₂R₂₃, —NR₂₂SO₂NR₂₃R₂₄, —C(═NR₂₂)NR₂₃R₂₄, fiveor six membered heterocyclo or heteroaryl, phenyl, and C₃₋₇cycloalkyl,provided that R₁₁ is not —C(═NR₂₂)NR₂₃R₂₄ when W is hydrogen; whereinwhen R₉, R₁₀ or R₁₁ is selected from heterocyclo, heteroaryl, phenyl,and C₃₋₇cycloalkyl, each of said cyclic groups in turn is optionallysubstituted with up to three of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄ aminoalkyl, halogen, hydroxy, haloalkyl, haloalkoxy,amino, C₁₋₄ alkylamino, and/or cyano; R₁₂, R₁₃, R₁₄, R₁₈, R₁₉, R₂₂ R₂₃,and R₂₄ are independently selected from hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, andheterocyclo; R₁₅, R₂₀ and R₂₁ are independently selected from alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,cycloalkyl, and heterocyclo; R₁₆ is alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, heteroaryl, cycloalkyl, or heterocyclo; p is1 or 2; q is 1, 2 or 3; and u is 1 or 2; provided that when Z is phenyl,pyridyl or pyridazinyl, R₉, R₁₀ and/or R₁₁ are other than cyano or—C(═NR₂₂)NR₂₃R₂₄.
 3. A compound according to claim 2, wherein: X isselected from —OH, —O(phenyl), —O(benzyl), —NH(phenyl), and wherein eachphenyl or benzyl group is optionally subsituted with one to two R₂₅, Wis hydrogen or —(CH₂)_(q)—H; Z is selected from the group:

R₁ and R₂ are OR₁₂; R₉ is selected from hydrogen, halogen, alkyl,substituted alkyl, haloalkyl, haloalkoxy, cyano, nitro, —S(O)_(u)R₂₁,—NR₂₂SO₂R₂₁, —C(═O)NR₂₂R₂₃, —OR₂₂, —CO₂R₂₂, —C(═O)R₂₂, —SR₂₂, —NR₂₂R₂₃,—NR₂₂CO₂R₂₃, —NR₂₂C(═O)R₂₃, —NR₂₂C(═O)NR₂₃R₂₄, —SO₂NR₂₂R₂₃,—NR₂₂SO₂NR₂₃R₂₄, five or six membered heterocyclo or heteroaryl, phenyl,and C₃₋₇cycloalkyl; R₁₂, R₂₂, R₂₃ and R₂₄ are selected from hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl,heteroaryl, cycloalkyl, or heterocyclo; R₂₁ is selected from alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,cycloalkyl, and heterocyclo; R₂₅ at each occurrence is selected fromC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, halogen,hydroxy, haloalkyl, haloalkoxy, amino, C₁₋₄alkylamino, and/or cyano; qis 1, 2 or 3; s is 0, 1, or 2; and u is 1 or 2; provided that when Z isphenyl, R₉ and/or R₁₁ are other than cyano or —C(═NR₂₂)NR₂₃R₂₄.
 4. Acompound according to claim 1, or a stereoisomer or apharmaceutically-acceptable salt thereof, wherein the compound is offormula (Ib),

wherein: X is selected from —O(phenyl), —O(benzyl), and—NH(phenyl)-NH(benzyl), wherein each group X is optionally subsitutedwith one to two R₂₅, W is hydrogen or —(CH₂)_(q)—H; Z is selected fromthe group:

R₉ is independently selected from hydrogen, halogen, alkyl, aminoalkyl,hydroxyalkyl, haloalkyl, haloalkoxy, alkoxy, cyano, nitro, alkylamino,alkylthio, thioalkyl, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl),—C(═O)N(C₁₋₄alkyl)₂, five or six membered heterocyclo or heteroaryl,phenyl, and C₃₋₇cycloalkyl; R_(12a) and R_(12b) are independentlyselected from hydrogen, alkyl, substituted alkyl, phenyl, and benzyl;R₂₅ at each occurrence is selected from C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl,haloalkoxy, amino, C₁₋₄alkylamino, and/or cyano; p is 1 or 2; and s is0, 1 or 2; provided that when Z is phenyl, R₉ and/or R₁₁ are other thancyano or —C(═NR₂₂)NR₂₃R₂₄.
 5. A compound according to claim 1, or astereoisomer or a pharmaceutically-acceptable salt thereof, wherein Z isselected from:

Z₄ is fused to ring A comprising the common carbon atom C* and is

Z₅ is fused to ring A comprising the common carbon atom C* and isselected from:

Z₆ is fused to ring A comprising the common carbon atom C* and is

Z₇ is fused to ring A comprising the common carbon atom C* and isselected from:

Z₈ is fused to ring B comprising the common nitrogen atom N* and isselected from

Z₉ is CH or N; r is 0, 1, or 2; and s is 0, 1, 2, or
 3. 6. A compoundaccording to claim 1, or a stereoisomer or a pharmaceutically-acceptablesalt, hydrate or prodrug thereof, wherein Z is selected from:


7. A compound according to claim 1, or a stereoisomer or apharmaceutically-acceptable salt, hydrate or prodrug thereof, wherein R₁and R₂ are OR₁₂.
 8. A compound according to claim 7, or a stereoisomeror a pharmaceutically acceptable salt, hydrate or prodrug thereof,wherein R₁₂ is C₁₋₆alkyl, phenyl, or benzyl optionally substituted withone to two of halogen, cyano, haloalkyl, haloalkoxy, nitro, hydroxy,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, amino, NH(C₁₋₄alkyl), andN(C₁₋₄alkyl)₂.
 9. A compound according to claim 8, or a stereoisomer ora pharmaceutically-acceptable salt, hydrate or prodrug thereof, whereinW is hydrogen.
 10. A compound according to claim 9, or a stereoisomer ora pharmaceutically-acceptable salt, hydrate or prodrug thereof, whereinX is NH(phenyl), NH(benzyl), SO₂alkyl, or SO₂(phenyl) optionallysubstituted with one to two of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl, haloalkoxy, amino,C₁₋₄alkylamino, and/or cyano.
 11. A compound having the formula (Ib),

or a stereoisomer or a pharmaceutically-acceptable salt thereof,wherein: X is selected from —O(phenyl) optionally substituted with oneto two R₂₅, —O(benzyl) optionally substituted with one to two R₂₅,—NH(phenyl) optionally substituted with one to two R₂₅, and—NH(phenylalkyl) optionally substituted with one to two R₂₅; W ishydrogen or —(CH₂)_(q)—H; Z is selected from:

Z₁, Z₂ and Z₃ are selected from N and CR₉; Z₄ is fused to ring Acomprising the common carbon atom C* and is

Z₅ is fused to ring A comprising the common carbon atom C* and isselected from:

Z₆ is fused to ring A comprising the common carbon atom C* and is

Z₇ is fused to ring A comprising the common carbon atom C* and isselected from:

Z₈ is fused to ring B comprising the common nitrogen atom N* and isselected from

Z₉ is CH or N; R₉ and R₁₀ are independently selected from hydrogen,halogen, alkyl, substituted alkyl, haloalkyl, haloalkoxy, cyano, nitro,—S(O)_(u)R₂₁, —NR₂₂SO₂R₂₁, —C(═O)NR₂₂R₂₃, —OR₂₂, —CO₂R₂₂, —C(═O)R₂₂,—SR₂₂, —NR₂₂R₂₃, —NR₂₂CO₂R₂₃, —NR₂₂C(═O)R₂₃, —NR₂₂C(═O)NR₂₃R₂₄,—SO₂NR₂₂R₂₃, —NR₂₂SO₂NR₂₃R₂₄, —C(═NR₂₂)NR₂₃R₂₄, five or six memberedheterocyclo or heteroaryl, phenyl, and C₃₋₇cycloalkyl, provided that R₉and R₁₀ are not —C(═NR₂₂)NR₂₃R₂₄ when W is hydrogen; wherein when R₉ orR₁₀ is independently selected from heterocyclo, heteroaryl, phenyl, andC₃₋₇cycloalkyl, each of said cyclic groups in turn is optionallysubstituted with up to three of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl, haloalkoxy, amino,C₁₋₄alkylamino, and/or cyano; R₁₂, R_(12a), R_(12b), R₂₂ R₂₃, and R₂₄are independently selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, andheterocyclo; R₂₁ is selected from alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; R₂₅at each occurrence is selected from C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, halogen, hydroxy, haloalkyl,haloalkoxy, amino, C₁₋₄alkylamino, and/or cyano; p is 1 or 2; q is 1, 2or 3; r is 0, 1, or 2; s is 0, 1, 2, or 3; t is 1 or 2; and u is 1 or 2.12. A compound according to claim 11, or a stereoisomer or apharmaceutically-acceptable salt thereof, wherein Z is selected from


13. A compound according to claim 1, wherein: X is NR₅(benzyl)optionally substituted with one to two R₂₅; W is hydrogen; Z is

and R₂₅ at each occurrence is selected from halogen, cyano, nitro,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, substituted C₁₋₁₀alkyl, substitutedC₂₋₁₀alkenyl, —C(═O)NR₁₂R₁₃, —OR₁₂, —CO₂R₁₂, —C(═O)R₁₂, —SR₁₂,—S(O)_(t)R₁₅, —NR₁₂R₁₃, —NR₁₂SO₂R₁₅, —NR₁₄SO₂NR₁₂R₁₃, —NR₁₂CO₂R₁₃,—NR₁₂C(═O)R₁₃, —NR₁₄C(═O)NR₁₂R₁₃, —SO₂NR₁₂R₁₃, aryl, heteroaryl,cycloalkyl, and heterocyclo.
 14. A compound according to claim 13,wherein: Z is


15. A compound according to claim 13, wherein: Z is


16. A compound according to claim 1, wherein: X is OH; W is hydrogen;and Z is


17. A compound according to claim 16, wherein: Z is


18. A compound according to claim 16, wherein: Z is


19. A compound according to claim 1, wherein the compound is selectedfrom the group:2-(4-Aminomethyl-phenylamino)-N-benzyl-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide;7-{[Carboxy-(3-ethoxy-4-isopropoxy-phenyl)-methyl]-amino}-3,4-dihydro-1H-isoquinoline-2-carboxylicacidtert-butyl ester;[3-(tert-Butoxycarbonylamino-methyl)-phenylamino]-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid;(1-Amino-isoquinolin-6-ylamino)-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid;2-(1-Amino-isoquinolin-6-ylamino)-N-benzyl-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide;or a stereoisomer or a pharmaceutically-acceptable salt thereof.
 20. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1,or a stereoisomer or a pharmaceutically-acceptable salt thereof.
 21. Amethod for treating a thromboembolic disorder, comprising: administeringto a patient in need thereof a therapeutically effective amount of acompound of claim 1, or a stereoisomer or a pharmaceutically acceptablesalt thereof.
 22. A method according to claim 21, wherein thethromboembolic disorder is selected from the group consisting ofarterial cardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, and thromboembolic disorders in the chambersof the heart.
 23. A method according to claim 21, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, first myocardial infarction, recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom (a) prosthetic valves or other implants, (b) indwelling catheters,(c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.
 24. The pharmaceutical composition of claim 20further comprising at least one other therapeutic agent selected fromone or more of potassium channel openers, calcium channel blockers,sodium hydrogen exchanger inhibitors, antiarrhythmic agents,antiatherosclerotic agents, anticoagulants, antithrombotic agents,prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning.
 25. The pharmaceutical composition of claim 20wherein the at least one other therapeutic agent is an antihypertensiveagent selected from ACE inhibitors, AT-1 receptor antagonists, ETreceptor antagonists, dual ET/AII receptor antagonists, andvasopepsidase inhibitors, or an antithrombotic agent selected from anantiplatelet agent selected from GPIIb/IIIa blockers, P2Y₁ and P2Y₁₂antagonists, thromboxane receptor antagonists, and aspirin.
 26. A methodof treating a Factor VIIa-associated disorder comprising administeringan effective amount of at least one compound of claim 1, or astereoisomer or a pharmaceutically-acceptable salt thereof, to a patientin need thereof.
 27. The method of claim 26 wherein the FactorVIIa-associated disorder is selected from myocardial infarction,coronary artery disease, non-Q wave MI, congestive heart failure,cardiac arrhythmias, unstable angina, chronic stable angina,Prinzmetal's angina, high blood pressure, intermittent claudication, andperipheral occlusive arterial disease.